EP3954684A1 - Verfahren zur herstellung von hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen - Google Patents
Verfahren zur herstellung von hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen Download PDFInfo
- Publication number
- EP3954684A1 EP3954684A1 EP21181833.1A EP21181833A EP3954684A1 EP 3954684 A1 EP3954684 A1 EP 3954684A1 EP 21181833 A EP21181833 A EP 21181833A EP 3954684 A1 EP3954684 A1 EP 3954684A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- azabicyclo
- heptan
- cyclopropyl
- methoxy
- dichlorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 230000008569 process Effects 0.000 title abstract description 4
- 230000002503 metabolic effect Effects 0.000 title description 4
- 229940127517 Hormone Receptor Modulators Drugs 0.000 title 1
- 125000001072 heteroaryl group Chemical group 0.000 claims description 515
- 229910052736 halogen Inorganic materials 0.000 claims description 379
- 150000002367 halogens Chemical group 0.000 claims description 378
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 324
- 125000003118 aryl group Chemical group 0.000 claims description 265
- 150000001875 compounds Chemical class 0.000 claims description 214
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 185
- -1 -(CH2)n-cycloalkyl Chemical group 0.000 claims description 146
- 150000003839 salts Chemical class 0.000 claims description 125
- 125000001424 substituent group Chemical group 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 105
- 125000004429 atom Chemical group 0.000 claims description 98
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 55
- 125000001188 haloalkyl group Chemical group 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 43
- 239000000543 intermediate Substances 0.000 claims description 39
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 16
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- NJBWADBNAYDDNZ-DVBNTOJCSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1 NJBWADBNAYDDNZ-DVBNTOJCSA-N 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- GGVBYTSVDNSZHT-CSODHUTKSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O GGVBYTSVDNSZHT-CSODHUTKSA-N 0.000 claims description 6
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- OILOVVDBTDBHTP-LLJLJFOGSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)O)F OILOVVDBTDBHTP-LLJLJFOGSA-N 0.000 claims description 5
- FLILWGMHGWPSHW-XZDHIHRUSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2-cyclopropyl-6-fluorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1F)C1CC1)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O FLILWGMHGWPSHW-XZDHIHRUSA-N 0.000 claims description 5
- SBSRXSIXMLIFPR-KHJUTWJGSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F SBSRXSIXMLIFPR-KHJUTWJGSA-N 0.000 claims description 5
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- YKVYEYYYLTUNNF-UYFZRMNSSA-N (2R)-6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1C=C2CC[C@H](CC2=CC=1)C(=O)O YKVYEYYYLTUNNF-UYFZRMNSSA-N 0.000 claims description 4
- YKVYEYYYLTUNNF-QHEFXJGPSA-N (2S)-6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1C=C2CC[C@@H](CC2=CC=1)C(=O)O YKVYEYYYLTUNNF-QHEFXJGPSA-N 0.000 claims description 4
- UZNZECXTAWJLPO-SGXKBVARSA-N 1-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]-2,2,2-trifluoroethanone Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C(C(F)(F)F)=O UZNZECXTAWJLPO-SGXKBVARSA-N 0.000 claims description 4
- WWTYWBLTNFOPRP-CTIGNXTNSA-N 1-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]cyclobutane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C1(CCC1)C(=O)O WWTYWBLTNFOPRP-CTIGNXTNSA-N 0.000 claims description 4
- QAGFNZAPIMEOOU-GERBCZOESA-N 1-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]cyclopropane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C1(CC1)C(=O)O QAGFNZAPIMEOOU-GERBCZOESA-N 0.000 claims description 4
- BPISVNITDMBXJS-OEZLWVFVSA-O 10-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoyl]sulfamoyl]decyl-diethyl-methylazanium Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(=O)NS(=O)(=O)CCCCCCCCCC[N+](C)(CC)CC)F BPISVNITDMBXJS-OEZLWVFVSA-O 0.000 claims description 4
- BYSCHCXVPBVVAT-UNIVCBNLSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-(7-oxaspiro[3.5]nonan-2-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1CC2(C1)CCOCC2)=O BYSCHCXVPBVVAT-UNIVCBNLSA-N 0.000 claims description 4
- RLHOTGSLEPOXAU-MFSJNOQSSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxan-4-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1CCOCC1)=O RLHOTGSLEPOXAU-MFSJNOQSSA-N 0.000 claims description 4
- RORKTHMJAWFFLR-GXZLPTSOSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxolan-3-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1COCC1)=O RORKTHMJAWFFLR-GXZLPTSOSA-N 0.000 claims description 4
- UIFVHMQHSYHIQU-VDVULAQNSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@@H]1COCC1)=O UIFVHMQHSYHIQU-VDVULAQNSA-N 0.000 claims description 4
- SCBOXUHTHGRECJ-LUQKVYGDSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-cyclopropyloxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)OC1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1=O)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O SCBOXUHTHGRECJ-LUQKVYGDSA-N 0.000 claims description 4
- UXGHAZJZICCIQA-CMKODMSKSA-N 2-[(1S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCCCC1)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F)C1CC1 UXGHAZJZICCIQA-CMKODMSKSA-N 0.000 claims description 4
- RYRIDIDULZSVDZ-ZUEVXXBESA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyrimidine-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=NC=C(C=N1)C(=O)O RYRIDIDULZSVDZ-ZUEVXXBESA-N 0.000 claims description 4
- RQRZMICOCRXFTL-HKARXFIJSA-N 2-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CC(=O)O)F RQRZMICOCRXFTL-HKARXFIJSA-N 0.000 claims description 4
- PFUVKDPIMDYMSY-WCAVRKLYSA-N 2-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]acetic acid Chemical compound OC(=O)Cc1ccc(cc1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 PFUVKDPIMDYMSY-WCAVRKLYSA-N 0.000 claims description 4
- QPQMGLZPSVFBKN-NJNPRVFISA-N 2-[[4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]amino]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C=C1)C(=O)NCC(=O)O)=O QPQMGLZPSVFBKN-NJNPRVFISA-N 0.000 claims description 4
- YSTLYLAXOLVEFK-YCRNBWNJSA-N 2-[[4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]amino]ethanesulfonic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C=C1)C(=O)NCCS(=O)(=O)O)=O YSTLYLAXOLVEFK-YCRNBWNJSA-N 0.000 claims description 4
- KZWSZGANNTZUBP-FOUYOVOOSA-N 2-[bis(2-hydroxyethyl)amino]ethyl 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]propanoate Chemical compound OCCN(CCO)CCOC(=O)CCc1ccc(N2C[C@@H]3C[C@H]2C[C@H]3OCc2c(onc2-c2c(Cl)cccc2Cl)C2CC2)c(F)c1 KZWSZGANNTZUBP-FOUYOVOOSA-N 0.000 claims description 4
- HJNKGPHXIIYXCA-GIMINZRKSA-N 2-cyano-4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C(#N)C1=C(C(=O)O)C=CC(=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1(CC1)F)C1=C(C=CC=C1Cl)Cl HJNKGPHXIIYXCA-GIMINZRKSA-N 0.000 claims description 4
- YRNPPWXQNBLKEE-TXBYWVTISA-N 2-cyano-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C(#N)C1=C(C(=O)O)C=CC(=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl YRNPPWXQNBLKEE-TXBYWVTISA-N 0.000 claims description 4
- DVNLWWQUBWURNH-WPSZSDGUSA-N 2-cyclopropyl-4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound OC(=O)c1ccc(cc1C1CC1)N1[C@@H]2C[C@@H](OCc3c(onc3-c3c(Cl)cccc3Cl)C3CC3)[C@@H](C2)C1=O DVNLWWQUBWURNH-WPSZSDGUSA-N 0.000 claims description 4
- LRPSBFFLYBTYTG-GDZNZVCISA-N 3-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,2-oxazole-5-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=NOC(=C1)C(=O)O LRPSBFFLYBTYTG-GDZNZVCISA-N 0.000 claims description 4
- GIMZJJQTKTVJET-ZYLNGJIFSA-N 3-[3-cyano-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]propanoic acid Chemical compound OC(=O)CCc1ccc(N2C[C@@H]3C[C@H]2C[C@H]3OCc2c(onc2-c2c(Cl)cccc2Cl)C2CC2)c(c1)C#N GIMZJJQTKTVJET-ZYLNGJIFSA-N 0.000 claims description 4
- RPAQONUHLCYFAP-YZZKKUAISA-N 3-[4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorophenyl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C=C1)CCC(=O)O)F)=O RPAQONUHLCYFAP-YZZKKUAISA-N 0.000 claims description 4
- XAKGJMPZOCLDNN-YGKZAACZSA-N 3-[4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)O)F)=O XAKGJMPZOCLDNN-YGKZAACZSA-N 0.000 claims description 4
- YDRDUSBWGQSJAQ-YCRNBWNJSA-N 3-[4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C=C1)CCC(=O)O)=O YDRDUSBWGQSJAQ-YCRNBWNJSA-N 0.000 claims description 4
- LXXTULDVBHOZOS-XHNVNVPESA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-methylsulfonylpropanamide Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C)F)C1CC1 LXXTULDVBHOZOS-XHNVNVPESA-N 0.000 claims description 4
- KUNATOHSKOOAQE-FOUYOVOOSA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-(oxan-4-ylsulfonyl)propanamide Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C1CCOCC1)F)C1CC1 KUNATOHSKOOAQE-FOUYOVOOSA-N 0.000 claims description 4
- QJHCWPHEVYCKBH-RXYILKCJSA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-cyclopropylsulfonylpropanamide Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C1CC1)F)C1CC1 QJHCWPHEVYCKBH-RXYILKCJSA-N 0.000 claims description 4
- CICNLWLKZNZFRD-ISJBWFOZSA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-methylsulfonylpropanamide Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C)F)C1CC1 CICNLWLKZNZFRD-ISJBWFOZSA-N 0.000 claims description 4
- DMYJPMNQNCUDDG-ZYLNGJIFSA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]propanoic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)O)F)C1CC1 DMYJPMNQNCUDDG-ZYLNGJIFSA-N 0.000 claims description 4
- YWVGHRYVSIIMPG-JVFUWBCBSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorophenyl]-2,2-dimethylpropanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C=C1)CC(C(=O)O)(C)C)F YWVGHRYVSIIMPG-JVFUWBCBSA-N 0.000 claims description 4
- WEVFDWCYYUQERZ-WVMBUTMQSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorophenyl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C=C1)CCC(=O)O)F WEVFDWCYYUQERZ-WVMBUTMQSA-N 0.000 claims description 4
- WYAPLXWQAQVPHU-IHMCZWCLSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-(oxan-4-ylsulfonyl)propanamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C1CCOCC1)F WYAPLXWQAQVPHU-IHMCZWCLSA-N 0.000 claims description 4
- YEQRABZQBMGXOP-OWOAZTCBSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-cyclopropylsulfonylpropanamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C1CC1)F YEQRABZQBMGXOP-OWOAZTCBSA-N 0.000 claims description 4
- JNGDBOLLQYJFCT-XHNVNVPESA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-methylsulfonylpropanamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C)F JNGDBOLLQYJFCT-XHNVNVPESA-N 0.000 claims description 4
- PQRWUPZZRZQHOT-OYSHIGHVSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]butanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(CC(=O)O)C)F PQRWUPZZRZQHOT-OYSHIGHVSA-N 0.000 claims description 4
- ITDVHHXXVCNZCV-UDCVSSOISA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]cyclobutane-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C1CC(C1)C(=O)O ITDVHHXXVCNZCV-UDCVSSOISA-N 0.000 claims description 4
- VAGXLMGXRJPIPD-VAXXYWNWSA-N 3-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)CCC(=O)O VAGXLMGXRJPIPD-VAXXYWNWSA-N 0.000 claims description 4
- OVWZTCKNYVVUPK-NJNPRVFISA-N 3-[5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]pyridin-2-yl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=CC(=NC=1)CCC(=O)O)=O OVWZTCKNYVVUPK-NJNPRVFISA-N 0.000 claims description 4
- VGWPRAJSEOSYQU-IUKKYPGJSA-N 3-cyano-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound OC(=O)c1ccc(N2C[C@@H]3C[C@H]2C[C@H]3OCc2c(onc2-c2c(Cl)cccc2Cl)C2CC2)c(c1)C#N VGWPRAJSEOSYQU-IUKKYPGJSA-N 0.000 claims description 4
- HZFXLRBBACQSSX-XHNVNVPESA-N 3-cyclopropyl-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C=1C=C(C(=O)O)C=CC=1N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl HZFXLRBBACQSSX-XHNVNVPESA-N 0.000 claims description 4
- AUFBASSZFXJCOC-MCFFVMPBSA-N 4-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2CN([C@@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F AUFBASSZFXJCOC-MCFFVMPBSA-N 0.000 claims description 4
- NNNZETBJQDQOAW-GAKIBJFNSA-N 4-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-3-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2CN([C@@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)C2CC2)C=C1)F NNNZETBJQDQOAW-GAKIBJFNSA-N 0.000 claims description 4
- XANJOMZBVPRADY-BSWQBHCVSA-N 4-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2CN([C@@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CC2)C=C1 XANJOMZBVPRADY-BSWQBHCVSA-N 0.000 claims description 4
- VGMHRRRFEZDLDU-CDMIOBSGSA-N 4-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2CN([C@@H](C1)C2)C1=CC=C(C(=O)O)C=C1 VGMHRRRFEZDLDU-CDMIOBSGSA-N 0.000 claims description 4
- SFZDJSUWOPEDMJ-CSODHUTKSA-N 4-[(1S,4R,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O)C1CC1 SFZDJSUWOPEDMJ-CSODHUTKSA-N 0.000 claims description 4
- MHJONBUQQDQZKA-NNMXDRDESA-N 4-[(1S,4R,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O)C1CC1 MHJONBUQQDQZKA-NNMXDRDESA-N 0.000 claims description 4
- PLVMFFJTJQGOMH-ZVUIFXONSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-(oxan-4-ylmethylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)CC2CCOCC2)C=C1)F)=O PLVMFFJTJQGOMH-ZVUIFXONSA-N 0.000 claims description 4
- BPBCNCPCJIVXEW-CNDUHNDJSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-(oxan-4-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1)F)=O BPBCNCPCJIVXEW-CNDUHNDJSA-N 0.000 claims description 4
- LCICOKVPQRWWMU-HCQTUCBBSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-(oxolan-3-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)C2COCC2)C=C1)F)=O LCICOKVPQRWWMU-HCQTUCBBSA-N 0.000 claims description 4
- AJHOKKJPPSMIBB-KYZSUZRRSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-[(1R,2R)-2-hydroxycyclopentyl]sulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)[C@H]2[C@@H](CCC2)O)C=C1)F)=O AJHOKKJPPSMIBB-KYZSUZRRSA-N 0.000 claims description 4
- HOXMWOYKAPVJGH-RZJRVXSHSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-[2-(oxolan-3-yl)ethylsulfonyl]benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)CCC2COCC2)C=C1)F)=O HOXMWOYKAPVJGH-RZJRVXSHSA-N 0.000 claims description 4
- KARKKWYBDWOLNT-PDSXEYIOSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F)=O KARKKWYBDWOLNT-PDSXEYIOSA-N 0.000 claims description 4
- DDJFPPNBPSMRIM-GSHUGGBRSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-methylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)C)=O DDJFPPNBPSMRIM-GSHUGGBRSA-N 0.000 claims description 4
- PQKDQLCXVIFLPN-QHWMMSMNSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylmethylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CC2CCOCC2)C=C1)=O PQKDQLCXVIFLPN-QHWMMSMNSA-N 0.000 claims description 4
- NDQKSLJONKQBGX-VUNYHOAISA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxolan-3-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2COCC2)C=C1)=O NDQKSLJONKQBGX-VUNYHOAISA-N 0.000 claims description 4
- GSJYLJJUNMSNGC-MBCOQLRTSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-[(1R,2R)-2-hydroxycyclopentyl]sulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)[C@H]2[C@@H](CCC2)O)C=C1)=O GSJYLJJUNMSNGC-MBCOQLRTSA-N 0.000 claims description 4
- MCKGMOGRKSOEGQ-IHBCGDQQSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-[2-(oxolan-3-yl)ethylsulfonyl]benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CCC2COCC2)C=C1)=O MCKGMOGRKSOEGQ-IHBCGDQQSA-N 0.000 claims description 4
- MYHPPLCYZRIBHD-LSRZYVKLSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-2-fluorobenzamide Chemical compound C1(CC1)S(=O)(=O)NC(C1=C(C=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1=O)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)F)=O MYHPPLCYZRIBHD-LSRZYVKLSA-N 0.000 claims description 4
- VQRVODDBCBWNDM-QZNHQXDQSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1C)C)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O VQRVODDBCBWNDM-QZNHQXDQSA-N 0.000 claims description 4
- BWBHCBZAFOUDIN-XZDHIHRUSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2-fluoro-6-propan-2-ylphenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound CC(C)c1cccc(F)c1-c1noc(C2CC2)c1CO[C@@H]1C[C@@H]2C[C@H]1C(=O)N2c1ccc(cc1)C(O)=O BWBHCBZAFOUDIN-XZDHIHRUSA-N 0.000 claims description 4
- GGVBYTSVDNSZHT-FVJLSDCUSA-N 4-[(1S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O GGVBYTSVDNSZHT-FVJLSDCUSA-N 0.000 claims description 4
- NPLPBHAVNMEOFM-NDIVSWGXSA-N 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-(oxan-4-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1)F NPLPBHAVNMEOFM-NDIVSWGXSA-N 0.000 claims description 4
- RPKXQULZWJCISZ-MZLICYQSSA-N 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F RPKXQULZWJCISZ-MZLICYQSSA-N 0.000 claims description 4
- OXFWKHIWIFJIHG-BCQCSXDESA-N 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-3-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)C2CC2)C=C1)F OXFWKHIWIFJIHG-BCQCSXDESA-N 0.000 claims description 4
- BCYILTKAFGSRFF-WFIHMLKPSA-N 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CC2)C=C1 BCYILTKAFGSRFF-WFIHMLKPSA-N 0.000 claims description 4
- CWCXIQMDFVRFTG-ODGPQVTHSA-N 4-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1 CWCXIQMDFVRFTG-ODGPQVTHSA-N 0.000 claims description 4
- HDTJWUIGFTXHBM-XLDJFRKUSA-N 4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)C1(CC1)F HDTJWUIGFTXHBM-XLDJFRKUSA-N 0.000 claims description 4
- ZSJFTUISWOPVKG-LLJLJFOGSA-N 4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-propylsulfonylbenzamide Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCC)C=C1)F)C1(CC1)F ZSJFTUISWOPVKG-LLJLJFOGSA-N 0.000 claims description 4
- FLIHZLZBHNRYIT-PONJGIIJSA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound OC(=O)c1ccc(N2C[C@@H]3C[C@H]2C[C@H]3OCc2c(onc2-c2c(F)cccc2Cl)C2CC2)c(F)c1 FLIHZLZBHNRYIT-PONJGIIJSA-N 0.000 claims description 4
- CAYKYFZVDBSBOW-SGXKBVARSA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)C1CC1 CAYKYFZVDBSBOW-SGXKBVARSA-N 0.000 claims description 4
- QHFVVXOCJGQFOC-GIMINZRKSA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)C1(CC1)F QHFVVXOCJGQFOC-GIMINZRKSA-N 0.000 claims description 4
- MVOXAFSJDIBADG-TXBYWVTISA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)C1CC1 MVOXAFSJDIBADG-TXBYWVTISA-N 0.000 claims description 4
- YOSVZVQILFYKJK-IUKKYPGJSA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F)C1CC1 YOSVZVQILFYKJK-IUKKYPGJSA-N 0.000 claims description 4
- QWEAKCTUQQXCER-SNUWEPMUSA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)benzamide Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1)C1CC1 QWEAKCTUQQXCER-SNUWEPMUSA-N 0.000 claims description 4
- AYCZZZDSANPMKQ-GREBRCKQSA-N 4-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)C1CC1 AYCZZZDSANPMKQ-GREBRCKQSA-N 0.000 claims description 4
- PUNSRKJSLWSPSE-PJSUUKDQSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2,3-difluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C(=C(C(=O)O)C=C1)F)F PUNSRKJSLWSPSE-PJSUUKDQSA-N 0.000 claims description 4
- SPHUFPMTQVTAGC-FBJOKTGGSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2,5-difluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1F)F SPHUFPMTQVTAGC-FBJOKTGGSA-N 0.000 claims description 4
- GUHVQVBEZJAJLH-DGCWBMGLSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2,6-difluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C(=C1)F)F GUHVQVBEZJAJLH-DGCWBMGLSA-N 0.000 claims description 4
- PBXDQYOBNUAWOE-XAPDGSRCSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2,6-difluorobenzonitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C#N)C(=C1)F)F PBXDQYOBNUAWOE-XAPDGSRCSA-N 0.000 claims description 4
- GZKPDTSPKGWKDB-FXJWSJNKSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-(2-methylsulfonylethyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)NCCS(=O)(=O)C)C=C1)F GZKPDTSPKGWKDB-FXJWSJNKSA-N 0.000 claims description 4
- ANANUNMLSHOFRL-HUOGWEQVSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-[2-(oxan-4-ylsulfonyl)ethyl]benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)NCCS(=O)(=O)C2CCOCC2)C=C1)F ANANUNMLSHOFRL-HUOGWEQVSA-N 0.000 claims description 4
- NUWUYDIFLNJZQU-FXJWSJNKSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-propylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)CCC)C=C1)F NUWUYDIFLNJZQU-FXJWSJNKSA-N 0.000 claims description 4
- SGNYJGFERZHFDI-GIMINZRKSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-methoxybenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)OC SGNYJGFERZHFDI-GIMINZRKSA-N 0.000 claims description 4
- WHDJTLADHUYLES-TXBYWVTISA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-methylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)C WHDJTLADHUYLES-TXBYWVTISA-N 0.000 claims description 4
- FXVSSIDHMZBBPX-AXHZCLLHSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-ethylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)CC FXVSSIDHMZBBPX-AXHZCLLHSA-N 0.000 claims description 4
- YBJSYYXLSLAYPO-NOMHHCBYSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-(3-methylbutylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCC(C)C)C=C1)F YBJSYYXLSLAYPO-NOMHHCBYSA-N 0.000 claims description 4
- KVRKHGSLJATIJP-ITAFUGMPSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-[10-[(2-methoxyacetyl)amino]decylsulfonyl]benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(=O)NS(=O)(=O)CCCCCCCCCCNC(COC)=O)F KVRKHGSLJATIJP-ITAFUGMPSA-N 0.000 claims description 4
- UCTPAUNZIHOFNC-FOUYOVOOSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-octylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCCCCCCC)C=C1)F UCTPAUNZIHOFNC-FOUYOVOOSA-N 0.000 claims description 4
- BDRUZPJWKDTTKO-NOMHHCBYSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-pentylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCCCC)C=C1)F BDRUZPJWKDTTKO-NOMHHCBYSA-N 0.000 claims description 4
- PFLVLVIYHGWLON-IUKKYPGJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-methylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)C PFLVLVIYHGWLON-IUKKYPGJSA-N 0.000 claims description 4
- ZUHNBYWMNKXEHE-QSJFZTKYSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(1-methylpiperidin-4-yl)sulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CCN(CC2)C)C=C1 ZUHNBYWMNKXEHE-QSJFZTKYSA-N 0.000 claims description 4
- OBRVGHUCQXGIIW-GGZJYHEGSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-cyclopropylsulfonylethyl)-2-fluorobenzamide Chemical compound Fc1cc(ccc1C(=O)NCCS(=O)(=O)C1CC1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 OBRVGHUCQXGIIW-GGZJYHEGSA-N 0.000 claims description 4
- GTLNEMUORLVYEI-VAXXYWNWSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-hydroxyethylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CCO)C=C1 GTLNEMUORLVYEI-VAXXYWNWSA-N 0.000 claims description 4
- MKBKGYCRDPNAOD-QYXIYQDXSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2-methylsulfonylethyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NCCS(=O)(=O)C)C=C1 MKBKGYCRDPNAOD-QYXIYQDXSA-N 0.000 claims description 4
- BAYITOPJNDLMCU-WCAVRKLYSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2H-tetrazol-5-ylmethyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NCC=2N=NNN=2)C=C1 BAYITOPJNDLMCU-WCAVRKLYSA-N 0.000 claims description 4
- ZRWTZPVJIHKNME-PDMSLNPASA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(3,4-dihydroxybutylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CCC(CO)O)C=C1 ZRWTZPVJIHKNME-PDMSLNPASA-N 0.000 claims description 4
- UXOIUNHEGGYDHC-TWAWCPDASA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(3-hydroxybutylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CCC(C)O)C=C1 UXOIUNHEGGYDHC-TWAWCPDASA-N 0.000 claims description 4
- YHHOAHBKJMMKGS-QYXIYQDXSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(3-hydroxypropylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CCCO)C=C1 YHHOAHBKJMMKGS-QYXIYQDXSA-N 0.000 claims description 4
- JHUHBWZTXMLMPT-JVFUWBCBSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxetan-3-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2COC2)C=C1 JHUHBWZTXMLMPT-JVFUWBCBSA-N 0.000 claims description 4
- KTBYHXYCCSDAPJ-XKHKYGQESA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxolan-3-ylmethylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CC2COCC2)C=C1 KTBYHXYCCSDAPJ-XKHKYGQESA-N 0.000 claims description 4
- LTOWNXIYJKXTSL-PDMSLNPASA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxolan-3-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2COCC2)C=C1 LTOWNXIYJKXTSL-PDMSLNPASA-N 0.000 claims description 4
- MIPIBQAXXCOTAF-RXYILKCJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-[2-(2-ethoxyethoxy)ethylsulfonyl]-3-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCOCCOCC)C=C1)F MIPIBQAXXCOTAF-RXYILKCJSA-N 0.000 claims description 4
- AXMRTHUSSJZQNJ-XOVJRCOKSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-2-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)C2CC2)C=C1)F AXMRTHUSSJZQNJ-XOVJRCOKSA-N 0.000 claims description 4
- PFDCFKMBLJAFBT-ITAFUGMPSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-dodecylsulfonyl-3-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCCCCCCCCCCC)C=C1)F PFDCFKMBLJAFBT-ITAFUGMPSA-N 0.000 claims description 4
- VQQXBVNALKZPEH-IUKKYPGJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-hydroxy-3-methylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NO)C=C1)C VQQXBVNALKZPEH-IUKKYPGJSA-N 0.000 claims description 4
- BPTAMSCIPHNKDQ-GIMINZRKSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzenesulfonic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)S(=O)(=O)O BPTAMSCIPHNKDQ-GIMINZRKSA-N 0.000 claims description 4
- KFLMXKMQLXGPTC-YZYLMMFTSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-oxido-2-azoniabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylbenzamide Chemical compound C1(CC1)S(=O)(=O)NC(=O)C1=CC=C(C=C1)[N+]1([C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)[O-] KFLMXKMQLXGPTC-YZYLMMFTSA-N 0.000 claims description 4
- FVCARIBZMJQARO-GTFJTEBLSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-oxido-2-azoniabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C(=O)(O)C1=CC=C(C=C1)[N+]1([C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)[O-] FVCARIBZMJQARO-GTFJTEBLSA-N 0.000 claims description 4
- IJYZDYLZRVEFHK-MZLICYQSSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1C)C)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F IJYZDYLZRVEFHK-MZLICYQSSA-N 0.000 claims description 4
- QANYOGAYERUNAT-ODGPQVTHSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1C)C)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1 QANYOGAYERUNAT-ODGPQVTHSA-N 0.000 claims description 4
- GIVNHUOQQRJYNC-CUVVAGTFSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-propylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCC)C=C1)F GIVNHUOQQRJYNC-CUVVAGTFSA-N 0.000 claims description 4
- PDPRFFKIDPWITH-HKARXFIJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F PDPRFFKIDPWITH-HKARXFIJSA-N 0.000 claims description 4
- XCRBJDUBIWTLHJ-WCAVRKLYSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1 XCRBJDUBIWTLHJ-WCAVRKLYSA-N 0.000 claims description 4
- HGFILKFNAGJEHV-XHNVNVPESA-N 4-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]butanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCCC(=O)O)F HGFILKFNAGJEHV-XHNVNVPESA-N 0.000 claims description 4
- ZSRITYJEABFBDE-QYXIYQDXSA-N 4-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]butanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)CCCC(=O)O ZSRITYJEABFBDE-QYXIYQDXSA-N 0.000 claims description 4
- OBPYFTZPPIULPL-YPAQECGVSA-N 4-[4-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]sulfamoyl]butan-2-yloxy]-4-oxobutanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C(=O)NS(=O)(=O)CCC(C)OC(CCC(=O)O)=O OBPYFTZPPIULPL-YPAQECGVSA-N 0.000 claims description 4
- KXJKAKOQDQAGEE-AQOAWAETSA-N 4-cyclopropyl-2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1=O)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O KXJKAKOQDQAGEE-AQOAWAETSA-N 0.000 claims description 4
- NFDWQYDCDBWTGS-RGZWJVDOSA-N 4-cyclopropyl-2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound OC(=O)c1ccc(cc1N1[C@@H]2C[C@@H](OCc3c(onc3-c3c(Cl)cccc3Cl)C3CC3)[C@@H](C2)C1=O)C1CC1 NFDWQYDCDBWTGS-RGZWJVDOSA-N 0.000 claims description 4
- FQWURSYOTRNDSW-VFFUXUAUSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2,3-dihydro-1H-indene-1-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C2CCC(C2=CC=1)C(=O)O)=O FQWURSYOTRNDSW-VFFUXUAUSA-N 0.000 claims description 4
- LEKAEMKDLSWLTE-DMJCMNNJSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)pyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)NS(=O)(=O)C1CCOCC1)=O LEKAEMKDLSWLTE-DMJCMNNJSA-N 0.000 claims description 4
- AZRUEJMPGNXUMU-WPKBUWHJSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]pyrimidine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=NC(=NC=1)C(=O)O)=O AZRUEJMPGNXUMU-WPKBUWHJSA-N 0.000 claims description 4
- HXWTXISBBSVPOY-TXBYWVTISA-N 5-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2,3-dihydroisoindol-1-one Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1C=C2CNC(C2=CC=1)=O HXWTXISBBSVPOY-TXBYWVTISA-N 0.000 claims description 4
- CTRVXVXBVSVSJJ-KHJUTWJGSA-N 5-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1C=CC2=C(NC(O2)=O)C=1 CTRVXVXBVSVSJJ-KHJUTWJGSA-N 0.000 claims description 4
- DAPSUKIPWFRMMO-FMKFIRIRSA-N 5-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3H-2-benzofuran-1-one Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC2=C(C(OC2)=O)C=C1 DAPSUKIPWFRMMO-FMKFIRIRSA-N 0.000 claims description 4
- YSWKDBVZLBRHDE-PONJGIIJSA-N 5-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-1-methylpyrazole-3-carboxamide Chemical compound C1(CC1)S(=O)(=O)NC(=O)C1=NN(C(=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C YSWKDBVZLBRHDE-PONJGIIJSA-N 0.000 claims description 4
- ZWVYJWFNEAKHTO-WDUKFBBWSA-N 5-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)O ZWVYJWFNEAKHTO-WDUKFBBWSA-N 0.000 claims description 4
- IXUZEPBGVMXFON-PONJGIIJSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[[(1S,4S,5R)-2-[2-fluoro-4-(2H-tetrazol-5-yl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl]oxymethyl]-1,2-oxazole Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C=1N=NNN=1)F IXUZEPBGVMXFON-PONJGIIJSA-N 0.000 claims description 4
- MWTFJJTVWGVBLI-LLJLJFOGSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[[(1S,4S,5R)-2-[2-fluoro-4-[2-(2H-tetrazol-5-yl)ethyl]phenyl]-2-azabicyclo[2.2.1]heptan-5-yl]oxymethyl]-1,2-oxazole Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC=1N=NNN=1)F MWTFJJTVWGVBLI-LLJLJFOGSA-N 0.000 claims description 4
- KWONZQOTMKZANJ-QMTMVMCOSA-N 6-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C=N1)C(=O)O)=O KWONZQOTMKZANJ-QMTMVMCOSA-N 0.000 claims description 4
- ALJHXSPBRCLDAV-WVMBUTMQSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3,4-dihydro-2H-isoquinolin-1-one Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1C=C2CCNC(C2=CC=1)=O ALJHXSPBRCLDAV-WVMBUTMQSA-N 0.000 claims description 4
- LSCYOEULRMCTPC-IUKKYPGJSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-5-fluoro-N-propylsulfonylpyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=NC=C(C(=O)NS(=O)(=O)CCC)C=C1F LSCYOEULRMCTPC-IUKKYPGJSA-N 0.000 claims description 4
- OBWUODUAJMZBPP-AUSJPIAWSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-5-fluoropyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=N1)C(=O)O)F OBWUODUAJMZBPP-AUSJPIAWSA-N 0.000 claims description 4
- YBENMMOOQGLUQR-HKARXFIJSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-5-fluoropyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=NC=C(C(=O)NS(=O)(=O)C2CC2)C=C1F YBENMMOOQGLUQR-HKARXFIJSA-N 0.000 claims description 4
- CUEKQTRUINRACE-IUKKYPGJSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylpyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=NC=C(C(=O)NS(=O)(=O)C2CC2)C=C1 CUEKQTRUINRACE-IUKKYPGJSA-N 0.000 claims description 4
- PZWPEDSNIAVEAP-SFYKDHMMSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-propylsulfonylpyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=NC=C(C(=O)NS(=O)(=O)CCC)C=C1 PZWPEDSNIAVEAP-SFYKDHMMSA-N 0.000 claims description 4
- VAXGJHYHJOLIIL-ITAFUGMPSA-N N-(10-acetamidodecylsulfonyl)-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(=O)NS(=O)(=O)CCCCCCCCCCNC(C)=O)F VAXGJHYHJOLIIL-ITAFUGMPSA-N 0.000 claims description 4
- NSSJYPAFQXROPB-QSJFZTKYSA-N N-(benzenesulfonyl)-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2=CC=CC=C2)C=C1 NSSJYPAFQXROPB-QSJFZTKYSA-N 0.000 claims description 4
- DNSZWJDRPYIADQ-HEKZAOSPSA-N N-cyclobutylsulfonyl-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzamide Chemical compound C1(CCC1)S(=O)(=O)NC(C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)=O DNSZWJDRPYIADQ-HEKZAOSPSA-N 0.000 claims description 4
- GJBNSXIVZVNFFB-QSJFZTKYSA-N N-cyclohexylsulfonyl-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzamide Chemical compound C1(CCCCC1)S(=O)(=O)NC(C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)=O GJBNSXIVZVNFFB-QSJFZTKYSA-N 0.000 claims description 4
- BXKNADRBUYGKPG-UNIVCBNLSA-N N-cyclopentylsulfonyl-4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzamide Chemical compound C1(CCCC1)S(=O)(=O)NC(C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1=O)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)=O BXKNADRBUYGKPG-UNIVCBNLSA-N 0.000 claims description 4
- ANTZDLPFNVEJAK-WOGXIUBCSA-N N-cyclopropylsulfonyl-4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzamide Chemical compound C1(CC1)S(=O)(=O)NC(C1=CC(=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1(CC1)F)C1=C(C=CC=C1Cl)Cl)F)=O ANTZDLPFNVEJAK-WOGXIUBCSA-N 0.000 claims description 4
- JGSWJFRAKHSJGN-WVMBUTMQSA-N N-cyclopropylsulfonyl-4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzamide Chemical compound C1(CC1)S(=O)(=O)NC(C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1(CC1)F)C1=C(C=CC=C1Cl)Cl)=O JGSWJFRAKHSJGN-WVMBUTMQSA-N 0.000 claims description 4
- QLVGQXMXWWHJFN-LZJCXSABSA-N N-cyclopropylsulfonyl-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)C2CC2)C=C1)F QLVGQXMXWWHJFN-LZJCXSABSA-N 0.000 claims description 4
- CQIIBQWCLFLKCY-PNLZDCPESA-N N-cyclopropylsulfonyl-6-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3-carboxamide Chemical compound FC1(CC1)c1onc(c1CO[C@@H]1C[C@@H]2C[C@H]1CN2c1ccc(cn1)C(=O)NS(=O)(=O)C1CC1)-c1c(Cl)cccc1Cl CQIIBQWCLFLKCY-PNLZDCPESA-N 0.000 claims description 4
- JKZFUWXFATUIID-PONJGIIJSA-N [(1S,4S,5R)-2-[4-(cyclopropylsulfonylcarbamoyl)-2-fluorophenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carboxylate Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(NS(=O)(=O)C1CC1)=O)F)C1(CC1)F JKZFUWXFATUIID-PONJGIIJSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- KNIOVRXWVHSXFJ-HBUWYVDXSA-N 2-[(1R,4R,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@H]2CN([C@@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F KNIOVRXWVHSXFJ-HBUWYVDXSA-N 0.000 claims description 3
- PJRPSXWROZRTAZ-STXHMFSFSA-N 2-[(1R,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@H]2CN([C@@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F PJRPSXWROZRTAZ-STXHMFSFSA-N 0.000 claims description 3
- KNIOVRXWVHSXFJ-LBTNJELSSA-N 2-[(1R,4R,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)c1cc(F)c2nc(sc2c1)N1C[C@H]2C[C@@H]1C[C@@H]2OC(=O)c1c(onc1-c1c(Cl)cccc1Cl)C1CC1 KNIOVRXWVHSXFJ-LBTNJELSSA-N 0.000 claims description 3
- PJRPSXWROZRTAZ-SXGZJXTBSA-N 2-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2CN([C@@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F PJRPSXWROZRTAZ-SXGZJXTBSA-N 0.000 claims description 3
- NHXVIDBJDHFWQI-UZCIPKQKSA-N 2-[(1R,4S,6R)-6-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@@H]1C[C@H]2CN([C@@H]1C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F NHXVIDBJDHFWQI-UZCIPKQKSA-N 0.000 claims description 3
- JYLAEYURDJPOBR-NXXCRTJYSA-N 2-[(1R,4S,6R)-6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1C[C@H]2CN([C@@H]1C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F JYLAEYURDJPOBR-NXXCRTJYSA-N 0.000 claims description 3
- NHXVIDBJDHFWQI-PDSMFRHLSA-N 2-[(1R,4S,6S)-6-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1C[C@H]2CN([C@@H]1C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F NHXVIDBJDHFWQI-PDSMFRHLSA-N 0.000 claims description 3
- IADKRYDPXBUZFQ-CSODHUTKSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-ethyl-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)CC)=O IADKRYDPXBUZFQ-CSODHUTKSA-N 0.000 claims description 3
- VPIXEYMDAYAIPO-PWXDABJZSA-N 2-[(1S,4S,5R)-5-[3-(1-bicyclo[2.2.2]octanyl)-5-cyclopropyl-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C12(CCC(CC1)CC2)C1=NOC(=C1C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F)C1CC1 VPIXEYMDAYAIPO-PWXDABJZSA-N 0.000 claims description 3
- WEAYDLGKKWCNRJ-GDZNZVCISA-N 2-[(1S,4S,5R)-5-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F)C1(CC1)F WEAYDLGKKWCNRJ-GDZNZVCISA-N 0.000 claims description 3
- PSUANKUWDADBGN-YZVOILCLSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C=CC(=C2)C(=O)O PSUANKUWDADBGN-YZVOILCLSA-N 0.000 claims description 3
- SOSBAGVHJSKBFQ-GRDNDAEWSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F SOSBAGVHJSKBFQ-GRDNDAEWSA-N 0.000 claims description 3
- SRADUTJHLQMWFD-SUNYJGFJSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethyl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C(F)(F)F SRADUTJHLQMWFD-SUNYJGFJSA-N 0.000 claims description 3
- BIXZBQMJIITPJR-TXPKVOOTSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-ethoxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OCC BIXZBQMJIITPJR-TXPKVOOTSA-N 0.000 claims description 3
- KNIOVRXWVHSXFJ-SUNYJGFJSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F KNIOVRXWVHSXFJ-SUNYJGFJSA-N 0.000 claims description 3
- RYZNHFCKHXAJNW-TXPKVOOTSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C RYZNHFCKHXAJNW-TXPKVOOTSA-N 0.000 claims description 3
- DYSBQDCBFMBGFG-SUNYJGFJSA-N 2-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F)C1(CC1)F DYSBQDCBFMBGFG-SUNYJGFJSA-N 0.000 claims description 3
- NNJISFRQWPGSFG-YZVOILCLSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F NNJISFRQWPGSFG-YZVOILCLSA-N 0.000 claims description 3
- CLTULJJYPQTSKL-AUSJPIAWSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethyl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C(F)(F)F CLTULJJYPQTSKL-AUSJPIAWSA-N 0.000 claims description 3
- XBLIMPHGFQXHDU-XGHQBKJUSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-ethoxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OCC XBLIMPHGFQXHDU-XGHQBKJUSA-N 0.000 claims description 3
- PJRPSXWROZRTAZ-AUSJPIAWSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F PJRPSXWROZRTAZ-AUSJPIAWSA-N 0.000 claims description 3
- FNVANRILTIEIIQ-CKJXQJPGSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-N-methylsulfonyl-1,3-benzothiazole-6-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)NS(=O)(=O)C)F FNVANRILTIEIIQ-CKJXQJPGSA-N 0.000 claims description 3
- ZLTJFIIZOFVNGA-IUKKYPGJSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-N-propylsulfonyl-1,3-benzothiazole-6-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)NS(=O)(=O)CCC)F ZLTJFIIZOFVNGA-IUKKYPGJSA-N 0.000 claims description 3
- OSJHBESRSYUXLF-XGHQBKJUSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C OSJHBESRSYUXLF-XGHQBKJUSA-N 0.000 claims description 3
- QMTFKFKEIBGIHQ-HKARXFIJSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-4-fluoro-1,3-benzothiazole-6-carboxamide Chemical compound C1(CC1)S(=O)(=O)NC(=O)C1=CC2=C(N=C(S2)N2[C@@H]3C[C@H]([C@H](C2)C3)OCC=2C(=NOC=2C2CC2)C2=C(C=CC=C2Cl)Cl)C(=C1)F QMTFKFKEIBGIHQ-HKARXFIJSA-N 0.000 claims description 3
- RICCUPUAUUDGAN-JENIJYKNSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(oxan-4-yl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1CCOCC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F RICCUPUAUUDGAN-JENIJYKNSA-N 0.000 claims description 3
- QRVYFIJLUBCWGB-TWOQFEAHSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F QRVYFIJLUBCWGB-TWOQFEAHSA-N 0.000 claims description 3
- PUDIWNTYLPQRCM-CKJXQJPGSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F PUDIWNTYLPQRCM-CKJXQJPGSA-N 0.000 claims description 3
- PSUANKUWDADBGN-DOXZYTNZSA-N 2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C=CC(=C2)C(=O)O PSUANKUWDADBGN-DOXZYTNZSA-N 0.000 claims description 3
- KNIOVRXWVHSXFJ-DEYYWGMASA-N 2-[(1S,4S,5S)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F KNIOVRXWVHSXFJ-DEYYWGMASA-N 0.000 claims description 3
- PJRPSXWROZRTAZ-AVYPCKFXSA-N 2-[(1S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F PJRPSXWROZRTAZ-AVYPCKFXSA-N 0.000 claims description 3
- UTUUAZDYMAFLHD-IHMCZWCLSA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-(oxan-4-ylsulfonyl)propanamide Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C1CCOCC1)F)C1CC1 UTUUAZDYMAFLHD-IHMCZWCLSA-N 0.000 claims description 3
- UIWYRMDAIIVLLX-OWOAZTCBSA-N 3-[4-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorophenyl]-N-cyclopropylsulfonylpropanamide Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)NS(=O)(=O)C1CC1)F)C1CC1 UIWYRMDAIIVLLX-OWOAZTCBSA-N 0.000 claims description 3
- RVUMLQVRXJJWJM-QZAGPXIQSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluoro-N-(oxolan-3-ylmethylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)CC2COCC2)C=C1)F)=O RVUMLQVRXJJWJM-QZAGPXIQSA-N 0.000 claims description 3
- WNNCCKKSIXKTEU-ICUDHFQXSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2,2-dimethyloxan-4-yl)sulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CC(OCC2)(C)C)C=C1)=O WNNCCKKSIXKTEU-ICUDHFQXSA-N 0.000 claims description 3
- SGDNKXKVUROMEG-UNIVCBNLSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1)=O SGDNKXKVUROMEG-UNIVCBNLSA-N 0.000 claims description 3
- ZEDKKGYCZDXHRN-CKFHNAJUSA-N 4-[(1S,4S,5R)-5-[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F)C1(CC1)F ZEDKKGYCZDXHRN-CKFHNAJUSA-N 0.000 claims description 3
- KMDNTDNAAPVYRM-AUSJPIAWSA-N 4-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F KMDNTDNAAPVYRM-AUSJPIAWSA-N 0.000 claims description 3
- SBKNMUQTQLDMHC-RIFZZMRRSA-N 4-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1 SBKNMUQTQLDMHC-RIFZZMRRSA-N 0.000 claims description 3
- JROVTBZVPYDYTF-VFCRVFHLSA-N 4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F)C1(CC1)F JROVTBZVPYDYTF-VFCRVFHLSA-N 0.000 claims description 3
- WXEFLGBDRYVJOT-HZUJVAHNSA-N 4-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)C1(CC1)F WXEFLGBDRYVJOT-HZUJVAHNSA-N 0.000 claims description 3
- KEDIBATZJGMNCP-VFCRVFHLSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3,5-difluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1F)F KEDIBATZJGMNCP-VFCRVFHLSA-N 0.000 claims description 3
- AUFBASSZFXJCOC-PONJGIIJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F AUFBASSZFXJCOC-PONJGIIJSA-N 0.000 claims description 3
- XANJOMZBVPRADY-JVFUWBCBSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylbenzamide Chemical compound Clc1cccc(Cl)c1-c1noc(C2CC2)c1CO[C@@H]1C[C@@H]2C[C@H]1CN2c1ccc(cc1)C(=O)NS(=O)(=O)C1CC1 XANJOMZBVPRADY-JVFUWBCBSA-N 0.000 claims description 3
- VAHAPCDQIKNKOA-QYXIYQDXSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-propylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CCC)C=C1 VAHAPCDQIKNKOA-QYXIYQDXSA-N 0.000 claims description 3
- VGMHRRRFEZDLDU-SGXKBVARSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1 VGMHRRRFEZDLDU-SGXKBVARSA-N 0.000 claims description 3
- CQRKLEOKBIKORC-IUKKYPGJSA-N 4-cyclopropyl-2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)c1cc(C2CC2)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 CQRKLEOKBIKORC-IUKKYPGJSA-N 0.000 claims description 3
- XAOKTOFXMNSNHS-HNYHFCPPSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2,3-dihydro-1H-indene-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C2CC(CC2=CC=1)C(=O)O)=O XAOKTOFXMNSNHS-HNYHFCPPSA-N 0.000 claims description 3
- NSLLHHXDTASPTB-AUSJPIAWSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[[(1S,4S,5R)-2-[4-fluoro-6-(2H-tetrazol-5-yl)-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptan-5-yl]oxymethyl]-1,2-oxazole Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C=1N=NNN=1)F NSLLHHXDTASPTB-AUSJPIAWSA-N 0.000 claims description 3
- JEZCIGBSRSZRMS-YZVOILCLSA-N 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-[[(1S,4S,5R)-2-[6-(2H-tetrazol-5-yl)-4-(trifluoromethoxy)-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptan-5-yl]oxymethyl]-1,2-oxazole Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C=1N=NNN=1)OC(F)(F)F JEZCIGBSRSZRMS-YZVOILCLSA-N 0.000 claims description 3
- YZZVZVVHAAEILY-TWOQFEAHSA-N 6-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=N1)C(=O)O YZZVZVVHAAEILY-TWOQFEAHSA-N 0.000 claims description 3
- HDNVDWQYVOHCHL-VAXXYWNWSA-N N-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]methyl]-N-hydroxyformamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)CN(C=O)O HDNVDWQYVOHCHL-VAXXYWNWSA-N 0.000 claims description 3
- XJFGKCQICJVPSY-AUSJPIAWSA-N [(1S,4S,5R)-2-[2-fluoro-4-(2H-tetrazol-5-yl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound Fc1cc(ccc1N1C[C@@H]2C[C@H]1C[C@H]2OC(=O)c1c(onc1-c1c(Cl)cccc1Cl)C1CC1)-c1nn[nH]n1 XJFGKCQICJVPSY-AUSJPIAWSA-N 0.000 claims description 3
- BXSGXOSBGMGFLJ-IUKKYPGJSA-N [(1S,4S,5R)-2-[2-fluoro-4-(propylsulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(NS(=O)(=O)CCC)=O)F BXSGXOSBGMGFLJ-IUKKYPGJSA-N 0.000 claims description 3
- DULPKDLYLXEYRX-RIFZZMRRSA-N [(1S,4S,5R)-2-[4-(2H-tetrazol-5-yl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C=1N=NNN=1 DULPKDLYLXEYRX-RIFZZMRRSA-N 0.000 claims description 3
- MWYBSRXURLJNGH-WCAVRKLYSA-N [(1S,4S,5R)-2-[4-(cyclopropylsulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C(NS(=O)(=O)C1CC1)=O MWYBSRXURLJNGH-WCAVRKLYSA-N 0.000 claims description 3
- KQQRZAOASPFICB-GREBRCKQSA-N [(1S,4S,5R)-2-[4-(propylsulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C(NS(=O)(=O)CCC)=O KQQRZAOASPFICB-GREBRCKQSA-N 0.000 claims description 3
- LTLPLDRRVNAPTB-YZVOILCLSA-N [(1S,4S,5R)-2-[4-fluoro-6-(methylsulfonylcarbamoyl)-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound CS(=O)(=O)NC(=O)c1cc(F)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@H]2OC(=O)c1c(onc1-c1c(Cl)cccc1Cl)C1CC1 LTLPLDRRVNAPTB-YZVOILCLSA-N 0.000 claims description 3
- ZNCWNWWVAIOTGU-XGHQBKJUSA-N [(1S,4S,5R)-2-[4-fluoro-6-(propylsulfonylcarbamoyl)-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound CCCS(=O)(=O)NC(=O)c1cc(F)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@H]2OC(=O)c1c(onc1-c1c(Cl)cccc1Cl)C1CC1 ZNCWNWWVAIOTGU-XGHQBKJUSA-N 0.000 claims description 3
- MSEQQVKBJCCFGJ-CKJXQJPGSA-N [(1S,4S,5R)-2-[6-(cyclopropylsulfonylcarbamoyl)-4-fluoro-1,3-benzothiazol-2-yl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound Fc1cc(cc2sc(nc12)N1C[C@@H]2C[C@H]1C[C@H]2OC(=O)c1c(onc1-c1c(Cl)cccc1Cl)C1CC1)C(=O)NS(=O)(=O)C1CC1 MSEQQVKBJCCFGJ-CKJXQJPGSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- XHGIYCUPVQCNIV-QYWGDWMGSA-N methyl 2-[(1S,4S,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate Chemical compound COC(=O)c1cc(F)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 XHGIYCUPVQCNIV-QYWGDWMGSA-N 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- UIFVHMQHSYHIQU-KCXPTXFHSA-N 2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@H]1COCC1)=O UIFVHMQHSYHIQU-KCXPTXFHSA-N 0.000 claims description 2
- QZTGEQRPHVJQAC-BBTUJRGHSA-N 2-[(1S,4S,5R)-5-[(3-cyclohexyl-5-cyclopropyl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCCCC1)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F)C1CC1 QZTGEQRPHVJQAC-BBTUJRGHSA-N 0.000 claims description 2
- URUBSJXKUYPYSQ-RLFYNMQTSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F URUBSJXKUYPYSQ-RLFYNMQTSA-N 0.000 claims description 2
- ZVMZECQPKMITEI-OMLFDEDXSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxolan-3-ylmethylsulfonyl)benzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)CC2COCC2)C=C1)=O ZVMZECQPKMITEI-OMLFDEDXSA-N 0.000 claims description 2
- VXBDFJIDZDWIEK-MFSJNOQSSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylbenzamide Chemical compound Clc1cccc(Cl)c1-c1noc(C2CC2)c1CO[C@@H]1C[C@@H]2C[C@H]1C(=O)N2c1ccc(cc1)C(=O)NS(=O)(=O)C1CC1 VXBDFJIDZDWIEK-MFSJNOQSSA-N 0.000 claims description 2
- QQBNUYLMKTUNDQ-NNMXDRDESA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2-fluoro-6-methylphenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1C)F)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O QQBNUYLMKTUNDQ-NNMXDRDESA-N 0.000 claims description 2
- JVOHQNJCGOZDRE-PONJGIIJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3,5-difluorobenzonitrile Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C#N)C=C1F)F JVOHQNJCGOZDRE-PONJGIIJSA-N 0.000 claims description 2
- VGYZTYFSSJWYBK-GEQKSPFYSA-N 4-cyclobutyl-2-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCC1)C1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1=O)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O VGYZTYFSSJWYBK-GEQKSPFYSA-N 0.000 claims description 2
- XGKRBNULVYDLIQ-VEVIJQCQSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]pyrazine-2-carboxylic acid Chemical compound OC(=O)c1cnc(cn1)N1[C@@H]2C[C@@H](OCc3c(onc3-c3c(Cl)cccc3Cl)C3CC3)[C@@H](C2)C1=O XGKRBNULVYDLIQ-VEVIJQCQSA-N 0.000 claims description 2
- DXIVMWPNWMVPPR-BXTJHSDWSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)O)=O DXIVMWPNWMVPPR-BXTJHSDWSA-N 0.000 claims description 2
- OJWLODSPMRSRTN-DVWYVKNESA-N 6-[(1R,3S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)pyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2[C@@H](N([C@@H](C1)C2)C1=CC=C(C=N1)C(=O)NS(=O)(=O)C1CCOCC1)C OJWLODSPMRSRTN-DVWYVKNESA-N 0.000 claims description 2
- SGGJCCNZYHFBAC-VEVIJQCQSA-N 6-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]pyridazine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(N=N1)C(=O)O)=O SGGJCCNZYHFBAC-VEVIJQCQSA-N 0.000 claims description 2
- LLJHKCVYDQKYRA-YYULODDRSA-N C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)O)F)=O)C1=C(C=CC=C1Cl)Cl Chemical compound C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=C(C=C(C=C1)CCC(=O)O)F)=O)C1=C(C=CC=C1Cl)Cl LLJHKCVYDQKYRA-YYULODDRSA-N 0.000 claims description 2
- FJOZQNJETAAMSE-NSLQWWKHSA-N C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1)F)=O)C1=C(C=CC=C1Cl)Cl Chemical compound C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)C2CCOCC2)C=C1)F)=O)C1=C(C=CC=C1Cl)Cl FJOZQNJETAAMSE-NSLQWWKHSA-N 0.000 claims description 2
- FFUMJBGLRQPIGV-XSSDXNQZSA-N C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)=O)C1=C(C=CC=C1Cl)Cl Chemical compound C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)=O)C1=C(C=CC=C1Cl)Cl FFUMJBGLRQPIGV-XSSDXNQZSA-N 0.000 claims description 2
- PWVHYVRELWJAEA-YZZKKUAISA-N C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O)C1=C(C=CC=C1Cl)Cl Chemical compound C1(CC1)C=1C=NN(C=1CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)=O)C1=C(C=CC=C1Cl)Cl PWVHYVRELWJAEA-YZZKKUAISA-N 0.000 claims description 2
- CNMFHDIDIMZHKY-UHFFFAOYSA-N methyl 2,2-dimethylpropanoate Chemical compound COC(=O)C(C)(C)C CNMFHDIDIMZHKY-UHFFFAOYSA-N 0.000 claims description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- HMTSIGCTUOHLIH-WVMBUTMQSA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]sulfonyl-methylamino]acetic acid Chemical compound CN(CC(O)=O)S(=O)(=O)c1ccc(cc1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 HMTSIGCTUOHLIH-WVMBUTMQSA-N 0.000 claims 2
- VQFHLMOLECJWFS-DUOBWASTSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2,2-dimethyloxan-4-yl)sulfonyl-2-fluorobenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)NS(=O)(=O)C2CC(OCC2)(C)C)C=C1)F)=O VQFHLMOLECJWFS-DUOBWASTSA-N 0.000 claims 2
- UPSKZVZSKHIITC-JVFUWBCBSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-(1H-pyrazol-4-ylsulfonyl)benzamide Chemical compound Clc1cccc(Cl)c1-c1noc(C2CC2)c1CO[C@@H]1C[C@@H]2C[C@H]1CN2c1ccc(cc1)C(=O)NS(=O)(=O)c1cn[nH]c1 UPSKZVZSKHIITC-JVFUWBCBSA-N 0.000 claims 2
- VLLBGUUASUNGNX-CKFHNAJUSA-N 6-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-5-fluoropyridine-3-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=N1)C(=O)O)F)C1(CC1)F VLLBGUUASUNGNX-CKFHNAJUSA-N 0.000 claims 2
- KRNFAIYHVNUTHR-AZRGUZCDSA-N N-[10-(azetidin-1-yl)decylsulfonyl]-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzamide Chemical compound Fc1cc(ccc1N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1)C(=O)NS(=O)(=O)CCCCCCCCCCN1CCC1 KRNFAIYHVNUTHR-AZRGUZCDSA-N 0.000 claims 2
- VULMIDGIHOZICM-NOMHHCBYSA-N N-butylsulfonyl-4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzamide Chemical compound C(CCC)S(=O)(=O)NC(C1=CC(=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1)C(F)(F)F)F)=O VULMIDGIHOZICM-NOMHHCBYSA-N 0.000 claims 2
- LDDOSDVZPSGLFZ-UHFFFAOYSA-N ethyl cyclopropanecarboxylate Chemical compound CCOC(=O)C1CC1 LDDOSDVZPSGLFZ-UHFFFAOYSA-N 0.000 claims 2
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 2
- ZOXRLYKCUYPCAC-RLFYNMQTSA-N 2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-(2,2,2-trifluoroethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OCC(F)(F)F ZOXRLYKCUYPCAC-RLFYNMQTSA-N 0.000 claims 1
- VUGNJEKAQCJQHC-CKFHNAJUSA-N 2-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)Cl)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F)C1(CC1)F VUGNJEKAQCJQHC-CKFHNAJUSA-N 0.000 claims 1
- ALVKPHCLLANZMY-XHNVNVPESA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-propylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)NS(=O)(=O)CCC)C=C1)F ALVKPHCLLANZMY-XHNVNVPESA-N 0.000 claims 1
- NNNZETBJQDQOAW-DPOKWSEZSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-3-fluorobenzamide Chemical compound Fc1cc(ccc1N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1)C(=O)NS(=O)(=O)C1CC1 NNNZETBJQDQOAW-DPOKWSEZSA-N 0.000 claims 1
- QSDHJDUMQOXGAC-WCAVRKLYSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-methylsulfonylbenzamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C(=O)NS(=O)(=O)C)C=C1 QSDHJDUMQOXGAC-WCAVRKLYSA-N 0.000 claims 1
- IKLMNSYGCLVNTN-XGHQBKJUSA-N 4-cyclopropyl-2-[(1S,4S,5R)-5-[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)c1cc(C2CC2)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@H]2OC(=O)c1c(onc1-c1c(Cl)cccc1Cl)C1CC1 IKLMNSYGCLVNTN-XGHQBKJUSA-N 0.000 claims 1
- OJWLODSPMRSRTN-QLQMMUPBSA-N 6-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)pyridine-3-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C1=CC=C(C=N1)C(=O)NS(=O)(=O)C1CCOCC1)C OJWLODSPMRSRTN-QLQMMUPBSA-N 0.000 claims 1
- IPJJCSRXGVYEBN-PGGSYOOXSA-N CS(=O)(=O)NC(=O)C1=CC(=C(C=C1)N2C[C@@H]3C[C@H]2C[C@H]3N4C(C(=C(O4)C5CC5)C(=O)O)C6=C(C=CC=C6Cl)Cl)F Chemical compound CS(=O)(=O)NC(=O)C1=CC(=C(C=C1)N2C[C@@H]3C[C@H]2C[C@H]3N4C(C(=C(O4)C5CC5)C(=O)O)C6=C(C=CC=C6Cl)Cl)F IPJJCSRXGVYEBN-PGGSYOOXSA-N 0.000 claims 1
- VPEUDXNVPLPNIO-RRYJXDLZSA-N CS(=O)(=O)NC(=O)C1=CC=C(C=C1)N2C[C@@H]3C[C@H]2C[C@H]3N4C(C(=C(O4)C5CC5)C(=O)O)C6=C(C=CC=C6Cl)Cl Chemical compound CS(=O)(=O)NC(=O)C1=CC=C(C=C1)N2C[C@@H]3C[C@H]2C[C@H]3N4C(C(=C(O4)C5CC5)C(=O)O)C6=C(C=CC=C6Cl)Cl VPEUDXNVPLPNIO-RRYJXDLZSA-N 0.000 claims 1
- GXHHGTYIIHYONW-KQXNSLOQSA-N NS([C@H](CCC1)[C@H]1C(C(F)=C(C=C1)C(O)=O)=C1N([C@@H](C[C@H]12)C[C@H]1OCC1=C(C3CC3)ON=C1C(C(Cl)=CC=C1)=C1Cl)C2=O)(=O)=O Chemical compound NS([C@H](CCC1)[C@H]1C(C(F)=C(C=C1)C(O)=O)=C1N([C@@H](C[C@H]12)C[C@H]1OCC1=C(C3CC3)ON=C1C(C(Cl)=CC=C1)=C1Cl)C2=O)(=O)=O GXHHGTYIIHYONW-KQXNSLOQSA-N 0.000 claims 1
- DYMLSOBXFGLJFF-PPZAAQBISA-N NS([C@H](CCC1)[C@H]1C(C=C(C=C1)N([C@@H](C[C@H]23)C[C@H]2OCC2=C(C4CC4)ON=C2C(C(Cl)=CC=C2)=C2Cl)C3=O)=C1C(O)=O)(=O)=O Chemical compound NS([C@H](CCC1)[C@H]1C(C=C(C=C1)N([C@@H](C[C@H]23)C[C@H]2OCC2=C(C4CC4)ON=C2C(C(Cl)=CC=C2)=C2Cl)C3=O)=C1C(O)=O)(=O)=O DYMLSOBXFGLJFF-PPZAAQBISA-N 0.000 claims 1
- GFZWHAAOIVMHOI-UHFFFAOYSA-N azetidine-3-carboxylic acid Chemical compound OC(=O)C1CNC1 GFZWHAAOIVMHOI-UHFFFAOYSA-N 0.000 claims 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims 1
- 229940090181 propyl acetate Drugs 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 89
- 201000010099 disease Diseases 0.000 abstract description 53
- 208000019423 liver disease Diseases 0.000 abstract description 40
- 208000017169 kidney disease Diseases 0.000 abstract description 38
- 208000023275 Autoimmune disease Diseases 0.000 abstract description 37
- 208000028774 intestinal disease Diseases 0.000 abstract description 36
- 239000012190 activator Substances 0.000 abstract description 13
- 206010038389 Renal cancer Diseases 0.000 abstract description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 abstract description 4
- 201000010982 kidney cancer Diseases 0.000 abstract description 4
- 125000005842 heteroatom Chemical group 0.000 description 258
- 229910052760 oxygen Inorganic materials 0.000 description 255
- 229910052717 sulfur Inorganic materials 0.000 description 255
- 229910052757 nitrogen Inorganic materials 0.000 description 254
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 244
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 223
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 137
- 235000002639 sodium chloride Nutrition 0.000 description 124
- 239000000651 prodrug Substances 0.000 description 117
- 229940002612 prodrug Drugs 0.000 description 117
- 239000012453 solvate Substances 0.000 description 116
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 111
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 105
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 102
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 93
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 79
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 71
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 67
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 59
- 239000003814 drug Substances 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 208000035475 disorder Diseases 0.000 description 36
- 206010028980 Neoplasm Diseases 0.000 description 35
- 239000003937 drug carrier Substances 0.000 description 35
- 238000004519 manufacturing process Methods 0.000 description 35
- 239000008194 pharmaceutical composition Substances 0.000 description 35
- 201000011510 cancer Diseases 0.000 description 34
- 239000002904 solvent Substances 0.000 description 31
- 230000002401 inhibitory effect Effects 0.000 description 27
- 150000004677 hydrates Chemical class 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 230000002265 prevention Effects 0.000 description 20
- 230000008030 elimination Effects 0.000 description 19
- 238000003379 elimination reaction Methods 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 19
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- 230000003213 activating effect Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 11
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 11
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000003613 bile acid Substances 0.000 description 11
- 229920003045 dextran sodium sulfate Polymers 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 230000004913 activation Effects 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 7
- 208000002551 irritable bowel syndrome Diseases 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 229910001868 water Inorganic materials 0.000 description 7
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 102100036334 Fragile X mental retardation syndrome-related protein 1 Human genes 0.000 description 6
- 101000930945 Homo sapiens Fragile X mental retardation syndrome-related protein 1 Proteins 0.000 description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 201000006417 multiple sclerosis Diseases 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 208000011231 Crohn disease Diseases 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 210000001072 colon Anatomy 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 229940121360 farnesoid X receptor (fxr) agonists Drugs 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 208000010157 sclerosing cholangitis Diseases 0.000 description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
- 125000006564 (C4-C8) cycloalkyl group Chemical group 0.000 description 4
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 4
- SLIIPXRYSFODBB-VMIIQTFKSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@H]1COCC1)C1CC1 SLIIPXRYSFODBB-VMIIQTFKSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 208000015943 Coeliac disease Diseases 0.000 description 4
- 206010009900 Colitis ulcerative Diseases 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 206010009887 colitis Diseases 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 208000037765 diseases and disorders Diseases 0.000 description 4
- 206010017758 gastric cancer Diseases 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 230000000770 proinflammatory effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- OBMATJWLQPFZLD-UHFFFAOYSA-N 1-cycloheptylazepan-3-ol Chemical compound OC1CN(CCCC1)C1CCCCCC1 OBMATJWLQPFZLD-UHFFFAOYSA-N 0.000 description 3
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 3
- BUXDRAWSEXSYHN-AQOAWAETSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-methylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)C)=O BUXDRAWSEXSYHN-AQOAWAETSA-N 0.000 description 3
- 208000003200 Adenoma Diseases 0.000 description 3
- 206010001233 Adenoma benign Diseases 0.000 description 3
- 102100038495 Bile acid receptor Human genes 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 206010008635 Cholestasis Diseases 0.000 description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
- 206010019629 Hepatic adenoma Diseases 0.000 description 3
- 101000979342 Homo sapiens Nuclear factor NF-kappa-B p105 subunit Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 208000002404 Liver Cell Adenoma Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 102100023050 Nuclear factor NF-kappa-B p105 subunit Human genes 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 description 3
- 239000004376 Sucralose Substances 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- HSMPNOSTRRTOND-KYZSUZRRSA-N [(1R,2R)-2-sulfamoylcyclopentyl] 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)O[C@H]2[C@@H](CCC2)S(N)(=O)=O)C=C1)F)=O HSMPNOSTRRTOND-KYZSUZRRSA-N 0.000 description 3
- MEVPKOIEXLIYIP-MBCOQLRTSA-N [(1R,2R)-2-sulfamoylcyclopentyl] 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]benzoate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC=C(C(=O)O[C@H]2[C@@H](CCC2)S(N)(=O)=O)C=C1)=O MEVPKOIEXLIYIP-MBCOQLRTSA-N 0.000 description 3
- 239000004305 biphenyl Chemical group 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000460 chlorine Chemical group 0.000 description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 230000004601 colonic permeability Effects 0.000 description 3
- 201000002758 colorectal adenoma Diseases 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 201000002735 hepatocellular adenoma Diseases 0.000 description 3
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 201000011549 stomach cancer Diseases 0.000 description 3
- 235000019408 sucralose Nutrition 0.000 description 3
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 230000002485 urinary effect Effects 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- SSYDWSGQUDLDIO-NDIWIEOSSA-N 1-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]methyl]azetidine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)CN1CC(C1)C(=O)O SSYDWSGQUDLDIO-NDIWIEOSSA-N 0.000 description 2
- AQGABGMEYTZFGE-UHFFFAOYSA-N 1-cycloheptylazepan-2-ol Chemical compound OC1CCCCCN1C1CCCCCC1 AQGABGMEYTZFGE-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- CZDSDPNLWAWUCQ-NLJOTIRTSA-N 2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxan-4-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(N=C(S2)N2C[C@@H]3C[C@H]2C[C@H]3OCC2=C(ON=C2C2CCC3(CC3)CC2)C2CC2)C(=C1)C1CCOCC1 CZDSDPNLWAWUCQ-NLJOTIRTSA-N 0.000 description 2
- CYFRIBWQGUHODY-PETUGJSASA-N 2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@@H]1COCC1 CYFRIBWQGUHODY-PETUGJSASA-N 0.000 description 2
- CYFRIBWQGUHODY-NANGSVCXSA-N 2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@H]1COCC1 CYFRIBWQGUHODY-NANGSVCXSA-N 0.000 description 2
- CEHATESOUWYYCD-CNNODRBYSA-N 2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1CCC2(CC2)CC1)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F CEHATESOUWYYCD-CNNODRBYSA-N 0.000 description 2
- GQGBWAXUCQGWIM-ZYLNGJIFSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxan-4-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1CCOCC1)C1CC1 GQGBWAXUCQGWIM-ZYLNGJIFSA-N 0.000 description 2
- PJPZZYUDYPKOLP-ZEMPLXOASA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC2=C(N=C(S2)N2C[C@@H]3C[C@H]2C[C@H]3OCC2=C(ON=C2C2=C(F)C=CC=C2Cl)C2CC2)C(=C1)[C@H]1CCOC1 PJPZZYUDYPKOLP-ZEMPLXOASA-N 0.000 description 2
- YUQUWAXGJFJLHD-PABYOWBDSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@H]1COCC1)C1CC1 YUQUWAXGJFJLHD-PABYOWBDSA-N 0.000 description 2
- PJPZZYUDYPKOLP-OETAKHSWSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@H]1COCC1)C1CC1 PJPZZYUDYPKOLP-OETAKHSWSA-N 0.000 description 2
- YUQUWAXGJFJLHD-KEXUJGGDSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@@H]1COCC1)C1CC1 YUQUWAXGJFJLHD-KEXUJGGDSA-N 0.000 description 2
- CGHKUXTUDVXQQV-XGHQBKJUSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-fluorophenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)F)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C)C1CC1 CGHKUXTUDVXQQV-XGHQBKJUSA-N 0.000 description 2
- MGWULNFNICKEBV-AOJNWGRGSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxan-4-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1CCOCC1)C1CC1 MGWULNFNICKEBV-AOJNWGRGSA-N 0.000 description 2
- SRMZGJMSQOLVPB-XZNRUFCYSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@@H]1COCC1)C1CC1 SRMZGJMSQOLVPB-XZNRUFCYSA-N 0.000 description 2
- SRMZGJMSQOLVPB-FKRYTKDZSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@H]1COCC1)C1CC1 SRMZGJMSQOLVPB-FKRYTKDZSA-N 0.000 description 2
- SLIIPXRYSFODBB-IBPRQYQWSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@@H]1COCC1)C1CC1 SLIIPXRYSFODBB-IBPRQYQWSA-N 0.000 description 2
- RXELSGOGSWKDNH-SFYKDHMMSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-cyclopropyloxy-1,3-benzothiazole-6-carboxylic acid Chemical compound ClC1=C(C(=CC=C1)C)C1=NOC(=C1CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC1CC1)C1CC1 RXELSGOGSWKDNH-SFYKDHMMSA-N 0.000 description 2
- UBDBTIZMOXBWLI-CNNODRBYSA-N 2-[(1S,4S,5R)-5-[[3-(2-chloro-6-methylphenyl)-5-cyclopropyl-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid Chemical compound CC1=CC(=CC2=C1N=C(S2)N1C[C@@H]2C[C@H]1C[C@H]2OCC1=C(ON=C1C1=C(C)C=CC=C1Cl)C1CC1)C(O)=O UBDBTIZMOXBWLI-CNNODRBYSA-N 0.000 description 2
- TVZSLCKGSRGTNP-PJSUUKDQSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichloro-4-hydroxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)O)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F TVZSLCKGSRGTNP-PJSUUKDQSA-N 0.000 description 2
- JAGZHTKTLRGDEF-VFCRVFHLSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichloro-4-methoxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=C(C=C1Cl)OC)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F JAGZHTKTLRGDEF-VFCRVFHLSA-N 0.000 description 2
- VTLZDJAUQWRMFE-DVBNTOJCSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(7-oxaspiro[3.5]nonan-2-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)c1cc(C2CC3(C2)CCOCC3)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 VTLZDJAUQWRMFE-DVBNTOJCSA-N 0.000 description 2
- MFFBHCOHZXHTFO-ZYLNGJIFSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxan-4-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1CCOCC1 MFFBHCOHZXHTFO-ZYLNGJIFSA-N 0.000 description 2
- BDOQYNJYCJWJCI-HPGKJDHSSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxepan-4-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1CCOCCC1 BDOQYNJYCJWJCI-HPGKJDHSSA-N 0.000 description 2
- CZUQSJSPNUBKOD-XFLLKONNSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(oxolan-3-yl)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C1COCC1 CZUQSJSPNUBKOD-XFLLKONNSA-N 0.000 description 2
- CZUQSJSPNUBKOD-ZEMPLXOASA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@@H]1COCC1 CZUQSJSPNUBKOD-ZEMPLXOASA-N 0.000 description 2
- LMJLXPNNERUPID-PABYOWBDSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3R)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@H]1COCC1 LMJLXPNNERUPID-PABYOWBDSA-N 0.000 description 2
- CZUQSJSPNUBKOD-OETAKHSWSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)[C@H]1COCC1 CZUQSJSPNUBKOD-OETAKHSWSA-N 0.000 description 2
- LMJLXPNNERUPID-KEXUJGGDSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-[(3S)-oxolan-3-yl]oxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)O[C@@H]1COCC1 LMJLXPNNERUPID-KEXUJGGDSA-N 0.000 description 2
- BRFVCSYQPUVFNM-PNLZDCPESA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-cyclopropyloxy-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)OC1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O BRFVCSYQPUVFNM-PNLZDCPESA-N 0.000 description 2
- XFIPGGDLGWRABT-NPPFBWRTSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-ethyl-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)CC XFIPGGDLGWRABT-NPPFBWRTSA-N 0.000 description 2
- SKEHTTWUTAPRGR-IUKKYPGJSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-propan-2-yl-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C(C)C SKEHTTWUTAPRGR-IUKKYPGJSA-N 0.000 description 2
- IMZMBUSJYUDFDJ-QNWVGRARSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dimethylphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-methyl-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1C)C)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)C IMZMBUSJYUDFDJ-QNWVGRARSA-N 0.000 description 2
- VTFNLCYBCXLHEP-CKJXQJPGSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2-hydroxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)O)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F VTFNLCYBCXLHEP-CKJXQJPGSA-N 0.000 description 2
- YNXZIUWZWXRPIP-PNLZDCPESA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2-methoxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)OC)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F YNXZIUWZWXRPIP-PNLZDCPESA-N 0.000 description 2
- KMSMCIJMNWXKNJ-XGHQBKJUSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(3-hydroxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=CC(=CC=C1)O)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F KMSMCIJMNWXKNJ-XGHQBKJUSA-N 0.000 description 2
- JZVGYUCXNVHXPB-NPPFBWRTSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(3-methoxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=CC(=CC=C1)OC)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F JZVGYUCXNVHXPB-NPPFBWRTSA-N 0.000 description 2
- ASAKRGONFYCIDS-XGHQBKJUSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(4-hydroxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=CC=C(C=C1)O)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F ASAKRGONFYCIDS-XGHQBKJUSA-N 0.000 description 2
- MAPSLGQENHMGSG-NPPFBWRTSA-N 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(4-methoxyphenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=CC=C(C=C1)OC)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)F MAPSLGQENHMGSG-NPPFBWRTSA-N 0.000 description 2
- NLHMQKABZPQZEB-VAXXYWNWSA-N 2-[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]phenyl]ethylphosphonic acid Chemical compound OP(O)(=O)CCc1ccc(cc1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 NLHMQKABZPQZEB-VAXXYWNWSA-N 0.000 description 2
- PMSQTKPHFIMNTJ-WSZRMNBISA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoyl]amino]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C=C1)C(=O)NCC(=O)O)F PMSQTKPHFIMNTJ-WSZRMNBISA-N 0.000 description 2
- NTRWKECFMGBZET-ZYLNGJIFSA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-methylbenzoyl]amino]ethylphosphonic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C=C1)C(=O)NCCP(O)(O)=O)C NTRWKECFMGBZET-ZYLNGJIFSA-N 0.000 description 2
- SUSYZLIQWAYWKK-WCAVRKLYSA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]amino]acetic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C(=O)NCC(=O)O SUSYZLIQWAYWKK-WCAVRKLYSA-N 0.000 description 2
- HEMNWPSTYFHFET-JEYPMZLKSA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]sulfamoyl]ethyl 2-methylpropanoate Chemical compound CC(C(=O)OCCS(=O)(=O)NC(=O)C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C HEMNWPSTYFHFET-JEYPMZLKSA-N 0.000 description 2
- UFQNLIGJEWSIAS-WDZJFXIESA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]sulfamoyl]ethyl acetate Chemical compound C(C)(=O)OCCS(=O)(=O)NC(=O)C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl UFQNLIGJEWSIAS-WDZJFXIESA-N 0.000 description 2
- LBTBMNDYUWEFRN-JEYPMZLKSA-N 2-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]sulfamoyl]ethyl cyclopropanecarboxylate Chemical compound C1(CC1)C(=O)OCCS(=O)(=O)NC(=O)C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl LBTBMNDYUWEFRN-JEYPMZLKSA-N 0.000 description 2
- IDUSJBBWEKNWAK-UHFFFAOYSA-N 3,4-dihydro-2h-1,2-benzothiazine Chemical compound C1=CC=C2SNCCC2=C1 IDUSJBBWEKNWAK-UHFFFAOYSA-N 0.000 description 2
- DTLFOYHVUIDKFB-GZWGPKMKSA-N 3-[5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoropyridin-2-yl]propanoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C(C(=NC=1)CCC(=O)O)F)=O DTLFOYHVUIDKFB-GZWGPKMKSA-N 0.000 description 2
- VWUXWNBJUDNBQN-JEYPMZLKSA-N 3-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]sulfamoyl]propyl acetate Chemical compound C(C)(=O)OCCCS(=O)(=O)NC(=O)C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl VWUXWNBJUDNBQN-JEYPMZLKSA-N 0.000 description 2
- WOZFMJHUURSHAR-FNPWNURISA-N 4-[(1R,3S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2[C@@H](N([C@@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F)C WOZFMJHUURSHAR-FNPWNURISA-N 0.000 description 2
- KUAWVQFLTRETDI-HXHYMRLSSA-N 4-[(1R,3S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2[C@@H](N([C@@H](C1)C2)C1=CC=C(C(=O)O)C=C1)C KUAWVQFLTRETDI-HXHYMRLSSA-N 0.000 description 2
- LNCLHMUGISYOHI-IZORYLLQSA-N 4-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-ethyl-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)CC LNCLHMUGISYOHI-IZORYLLQSA-N 0.000 description 2
- VLVAZFOXYXXKCV-WKHXIAAESA-N 4-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)C VLVAZFOXYXXKCV-WKHXIAAESA-N 0.000 description 2
- WOZFMJHUURSHAR-DXOGASHRSA-N 4-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)F)C WOZFMJHUURSHAR-DXOGASHRSA-N 0.000 description 2
- KUAWVQFLTRETDI-GGNOIXCSSA-N 4-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C1=CC=C(C(=O)O)C=C1)C KUAWVQFLTRETDI-GGNOIXCSSA-N 0.000 description 2
- NNNZETBJQDQOAW-DTECTHIISA-N 4-[(1S,4S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-3-fluorobenzamide Chemical compound O=C(C(C=C1)=CC(F)=C1N(C[C@@H]1C2)[C@@H]2CC1OCC1=C(C2CC2)ON=C1C(C(Cl)=CC=C1)=C1Cl)NS(C1CC1)(=O)=O NNNZETBJQDQOAW-DTECTHIISA-N 0.000 description 2
- QSDHJDUMQOXGAC-VGNWIJSDSA-N 4-[(1S,4S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-N-methylsulfonylbenzamide Chemical compound CS(NC(C(C=C1)=CC=C1N(C[C@@H]1C2)[C@@H]2CC1OCC1=C(C2CC2)ON=C1C(C(Cl)=CC=C1)=C1Cl)=O)(=O)=O QSDHJDUMQOXGAC-VGNWIJSDSA-N 0.000 description 2
- XDCALMVAZVXHNZ-PONJGIIJSA-N 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-3-(trifluoromethyl)benzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=C(C=C(C(=O)O)C=C1)C(F)(F)F XDCALMVAZVXHNZ-PONJGIIJSA-N 0.000 description 2
- BASNFTLGOCATQN-USYGNDFUSA-N 4-[[4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]benzoyl]sulfamoyl]butan-2-yl acetate Chemical compound C(C)(=O)OC(C)CCS(=O)(=O)NC(=O)C1=CC=C(C=C1)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl BASNFTLGOCATQN-USYGNDFUSA-N 0.000 description 2
- WMAZULNXANJOHE-IECBHUPTSA-N 4-cyclobutyl-2-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCC1)C1=CC(=CC2=C1N=C(S2)N1[C@H]2C[C@@H]([C@@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O WMAZULNXANJOHE-IECBHUPTSA-N 0.000 description 2
- OMLIZSQRJDHXBC-JCYRPKCISA-N 4-cyclobutyl-2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCC1)C1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1CCC2(CC2)CC1)C(=O)O OMLIZSQRJDHXBC-JCYRPKCISA-N 0.000 description 2
- WMAZULNXANJOHE-AXHZCLLHSA-N 4-cyclobutyl-2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCC1)C1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O WMAZULNXANJOHE-AXHZCLLHSA-N 0.000 description 2
- JWKBDAPPDWZQFR-FHAGJXEFSA-N 4-cyclopentyl-2-[(1R,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCCC1)C1=CC(=CC2=C1N=C(S2)N1[C@H]2C[C@@H]([C@@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O JWKBDAPPDWZQFR-FHAGJXEFSA-N 0.000 description 2
- MBHWSUBNUJUDEY-NLJOTIRTSA-N 4-cyclopentyl-2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CCCC1)C1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1CCC2(CC2)CC1)C(=O)O MBHWSUBNUJUDEY-NLJOTIRTSA-N 0.000 description 2
- JWKBDAPPDWZQFR-ZYLNGJIFSA-N 4-cyclopentyl-2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)c1cc(C2CCCC2)c2nc(sc2c1)N1C[C@@H]2C[C@H]1C[C@H]2OCc1c(onc1-c1c(Cl)cccc1Cl)C1CC1 JWKBDAPPDWZQFR-ZYLNGJIFSA-N 0.000 description 2
- HHCJFAZIPKFLIR-AWRGLXIESA-N 4-cyclopropyloxy-2-[(1S,4S,5R)-5-[(5-cyclopropyl-3-spiro[2.5]octan-6-yl-1,2-oxazol-4-yl)methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)OC1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1CCC2(CC2)CC1)C(=O)O HHCJFAZIPKFLIR-AWRGLXIESA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- MWXNLCSPTJUMJV-IUKKYPGJSA-N 4-tert-butyl-2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1,3-benzothiazole-6-carboxylic acid Chemical compound C(C)(C)(C)C1=CC(=CC2=C1N=C(S2)N1[C@@H]2C[C@H]([C@H](C1)C2)OCC=1C(=NOC=1C1CC1)C1=C(C=CC=C1Cl)Cl)C(=O)O MWXNLCSPTJUMJV-IUKKYPGJSA-N 0.000 description 2
- HYTOSIQWLDDTOS-WSBMPQEGSA-N 5-[(1R,3S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]-N-(oxan-4-ylsulfonyl)pyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2[C@@H](N([C@@H](C1)C2)C=1C=CC(=NC=1)C(=O)NS(=O)(=O)C1CCOCC1)C HYTOSIQWLDDTOS-WSBMPQEGSA-N 0.000 description 2
- DERIRYVIEZKZJA-VJESKBHDSA-N 5-[(1R,3S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2[C@@H](N([C@@H](C1)C2)C=1C=CC(=NC=1)C(=O)O)C DERIRYVIEZKZJA-VJESKBHDSA-N 0.000 description 2
- DERIRYVIEZKZJA-AYBUPXMNSA-N 5-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)O)C DERIRYVIEZKZJA-AYBUPXMNSA-N 0.000 description 2
- GHOWCLGXEUYKFX-WRMOXONVSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoro-N-[(1R,2R)-2-hydroxycyclopentyl]sulfonylpyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C(C(=NC=1)C(=O)NS(=O)(=O)[C@H]1[C@@H](CCC1)O)F)=O GHOWCLGXEUYKFX-WRMOXONVSA-N 0.000 description 2
- NPWLAPWWZOPIRX-BBEJJTJUSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-3-fluoropyridine-2-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C(C(=NC=1)C(=O)O)F)=O NPWLAPWWZOPIRX-BBEJJTJUSA-N 0.000 description 2
- RAMXZNHGCTVNFS-BRZSBKIASA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2,2-dimethyloxan-4-yl)sulfonyl-3-fluoropyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C(C(=NC=1)C(=O)NS(=O)(=O)C1CC(OCC1)(C)C)F)=O RAMXZNHGCTVNFS-BRZSBKIASA-N 0.000 description 2
- MHGNNMBOWDTLNY-OGSAEZJVSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-(2,2-dimethyloxan-4-yl)sulfonylpyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)NS(=O)(=O)C1CC(OCC1)(C)C)=O MHGNNMBOWDTLNY-OGSAEZJVSA-N 0.000 description 2
- CRBOOIUPVPYNPE-QJSKMURHSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-[(1R,2R)-2-hydroxycyclopentyl]sulfonylpyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)NS(=O)(=O)[C@H]1[C@@H](CCC1)O)=O CRBOOIUPVPYNPE-QJSKMURHSA-N 0.000 description 2
- UWCZJIBZVOQNAE-WTBBCNCBSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonyl-3-fluoropyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=C(C(=NC=1)C(=O)NS(=O)(=O)C1CC1)F)=O UWCZJIBZVOQNAE-WTBBCNCBSA-N 0.000 description 2
- PAFVPAWONIKEPL-PRCFCKQXSA-N 5-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-N-cyclopropylsulfonylpyridine-2-carboxamide Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C=1C=CC(=NC=1)C(=O)NS(=O)(=O)C1CC1)=O PAFVPAWONIKEPL-PRCFCKQXSA-N 0.000 description 2
- HLCZVGDTGVFWBA-CKFHNAJUSA-N 5-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-1-methylpyrazole-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=NN1C)C(=O)O HLCZVGDTGVFWBA-CKFHNAJUSA-N 0.000 description 2
- QZRGSPITJWYVRG-HKHONHPRSA-N 6-[(1R,3S,4R,5S)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@@H]1[C@H]2[C@@H](N([C@@H](C1)C2)C1=CC=C(C=N1)C(=O)O)C QZRGSPITJWYVRG-HKHONHPRSA-N 0.000 description 2
- QZRGSPITJWYVRG-UKHRCAFHSA-N 6-[(1S,3R,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-methyl-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2[C@H](N([C@H](C1)C2)C1=CC=C(C=N1)C(=O)O)C QZRGSPITJWYVRG-UKHRCAFHSA-N 0.000 description 2
- 201000011374 Alagille syndrome Diseases 0.000 description 2
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 2
- 206010070545 Bacterial translocation Diseases 0.000 description 2
- 108070000005 Bile acid receptors Proteins 0.000 description 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 description 2
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 2
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 2
- 206010010317 Congenital absence of bile ducts Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 102100036336 Fragile X mental retardation syndrome-related protein 2 Human genes 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 101000930952 Homo sapiens Fragile X mental retardation syndrome-related protein 2 Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 102100039364 Metalloproteinase inhibitor 1 Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000034486 Multi-organ failure Diseases 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- 238000011887 Necropsy Methods 0.000 description 2
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 102100022669 Nuclear receptor subfamily 5 group A member 2 Human genes 0.000 description 2
- 101710105538 Nuclear receptor subfamily 5 group A member 2 Proteins 0.000 description 2
- 206010062070 Peritonitis bacterial Diseases 0.000 description 2
- 208000002389 Pouchitis Diseases 0.000 description 2
- 206010036774 Proctitis Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 208000024780 Urticaria Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- KITLHDOXGPKSBS-CKJXQJPGSA-N [(1S,4S,5R)-2-[2-fluoro-4-(methylsulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound CS(=O)(=O)NC(=O)c1ccc(N2C[C@@H]3C[C@H]2C[C@H]3OC(=O)c2c(onc2-c2c(Cl)cccc2Cl)C2CC2)c(F)c1 KITLHDOXGPKSBS-CKJXQJPGSA-N 0.000 description 2
- QNHSKYOQNCDXQO-DJPFJPOOSA-N [(1S,4S,5R)-2-[4-(methylsulfonylcarbamoyl)phenyl]-2-azabicyclo[2.2.1]heptan-5-yl] 5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazole-4-carboxylate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)C(=O)O[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC=C(C=C1)C(NS(=O)(=O)C)=O QNHSKYOQNCDXQO-DJPFJPOOSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 230000007375 bacterial translocation Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 201000005271 biliary atresia Diseases 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- 125000005436 dihydrobenzothiophenyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000004613 furo[2,3-c]pyridinyl group Chemical group O1C(=CC=2C1=CN=CC2)* 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 239000000833 heterodimer Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- CRXFFXYNUARJQL-WSZRMNBISA-N methyl 4-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoate Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2CN([C@H](C1)C2)C1=CC(=C(C(=O)OC)C=C1)F CRXFFXYNUARJQL-WSZRMNBISA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 2
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 description 2
- 229960001601 obeticholic acid Drugs 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 210000003240 portal vein Anatomy 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 2
- RUUOPSRRIKJHNH-UHFFFAOYSA-N pyridazine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=N1 RUUOPSRRIKJHNH-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- VJVZPTPOYCJFNI-UHFFFAOYSA-M (2-ethoxy-2-oxoethyl)-triphenylphosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC(=O)OCC)C1=CC=CC=C1 VJVZPTPOYCJFNI-UHFFFAOYSA-M 0.000 description 1
- PAORVUMOXXAMPL-SECBINFHSA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride Chemical compound CO[C@](C(Cl)=O)(C(F)(F)F)C1=CC=CC=C1 PAORVUMOXXAMPL-SECBINFHSA-N 0.000 description 1
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 description 1
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- DMPZJACLHDWUFS-UHFFFAOYSA-N 1,3-benzothiazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2N=CSC2=C1 DMPZJACLHDWUFS-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 1
- URUBSJXKUYPYSQ-MPGHIAIKSA-N 2-[(1S,4S,5S)-5-[5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazole-4-carbonyl]oxy-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1)C(F)(F)F)C(=O)O[C@@H]1[C@@H]2CN([C@H](C1)C2)C=1SC2=C(N=1)C(=CC(=C2)C(=O)O)OC(F)(F)F URUBSJXKUYPYSQ-MPGHIAIKSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- BISCPIDPNKJGJT-GEQKSPFYSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-ethylbenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)CC)=O BISCPIDPNKJGJT-GEQKSPFYSA-N 0.000 description 1
- DZBSVVKTEWIOTB-CMPZQBNXSA-N 4-[(1S,4R,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2-fluorobenzoic acid Chemical compound C1(CC1)C1=C(C(=NO1)C1=C(C=CC=C1Cl)Cl)CO[C@H]1[C@@H]2C(N([C@H](C1)C2)C1=CC(=C(C(=O)O)C=C1)F)=O DZBSVVKTEWIOTB-CMPZQBNXSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- VERUFXOALATMPS-UHFFFAOYSA-N 5,5-diamino-2-(2-phenylethenyl)cyclohex-3-ene-1,1-disulfonic acid Chemical compound C1=CC(N)(N)CC(S(O)(=O)=O)(S(O)(=O)=O)C1C=CC1=CC=CC=C1 VERUFXOALATMPS-UHFFFAOYSA-N 0.000 description 1
- XAOKTOFXMNSNHS-WPQXDIDISA-N 5-[(1S,4R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl]-2,3-dihydro-1H-indene-2-carboxylic acid Chemical compound OC(C1CC2=CC(N([C@@H](C[C@H]34)CC3OCC3=C(C5CC5)ON=C3C(C(Cl)=CC=C3)=C3Cl)C4=O)=CC=C2C1)=O XAOKTOFXMNSNHS-WPQXDIDISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 101150103860 Akr1b7 gene Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 1
- 102000011772 Apolipoprotein C-I Human genes 0.000 description 1
- 108010076807 Apolipoprotein C-I Proteins 0.000 description 1
- 101710095339 Apolipoprotein E Proteins 0.000 description 1
- 102100029470 Apolipoprotein E Human genes 0.000 description 1
- 206010003645 Atopy Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 102100027950 Bile acid-CoA:amino acid N-acyltransferase Human genes 0.000 description 1
- 102100023109 Bile acyl-CoA synthetase Human genes 0.000 description 1
- 101710095877 Bile acyl-CoA synthetase Proteins 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010067969 Cholestatic liver injury Diseases 0.000 description 1
- 108090000943 Cholesterol 7-alpha-monooxygenases Proteins 0.000 description 1
- 102000004410 Cholesterol 7-alpha-monooxygenases Human genes 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 108010004103 Chylomicrons Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 102100038637 Cytochrome P450 7A1 Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012742 Diarrhoea infectious Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- BYTNEISLBIENSA-MDZDMXLPSA-N GW 4064 Chemical compound CC(C)C=1ON=C(C=2C(=CC=CC=2Cl)Cl)C=1COC(C=C1Cl)=CC=C1\C=C\C1=CC=CC(C(O)=O)=C1 BYTNEISLBIENSA-MDZDMXLPSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 102000058061 Glucose Transporter Type 4 Human genes 0.000 description 1
- 102100036264 Glucose-6-phosphatase catalytic subunit 1 Human genes 0.000 description 1
- 101710099339 Glucose-6-phosphatase catalytic subunit 1 Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 208000027761 Hepatic autoimmune disease Diseases 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 102000019267 Hepatic lipases Human genes 0.000 description 1
- 108050006747 Hepatic lipases Proteins 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 101000603876 Homo sapiens Bile acid receptor Proteins 0.000 description 1
- 101000697858 Homo sapiens Bile acid-CoA:amino acid N-acyltransferase Proteins 0.000 description 1
- 101000901154 Homo sapiens Complement C3 Proteins 0.000 description 1
- 101000957672 Homo sapiens Cytochrome P450 7A1 Proteins 0.000 description 1
- 101000826399 Homo sapiens Sulfotransferase 1A1 Proteins 0.000 description 1
- 101000826397 Homo sapiens Sulfotransferase 1A2 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000001479 Member 11 Subfamily B ATP Binding Cassette Transporter Human genes 0.000 description 1
- 108010093662 Member 11 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100390675 Mus musculus Fgf15 gene Proteins 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010051606 Necrotising colitis Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 241001504519 Papio ursinus Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 108090000472 Phosphoenolpyruvate carboxykinase (ATP) Proteins 0.000 description 1
- 102100034792 Phosphoenolpyruvate carboxykinase [GTP], mitochondrial Human genes 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 208000017855 Progressive familial intrahepatic cholestasis type 1 Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 108091006300 SLC2A4 Proteins 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 102100023986 Sulfotransferase 1A1 Human genes 0.000 description 1
- 102100023984 Sulfotransferase 1A2 Human genes 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- GUWTXVUFNXVQMT-UHFFFAOYSA-N [N]1C=2N(CCC1)C=CC2 Chemical compound [N]1C=2N(CCC1)C=CC2 GUWTXVUFNXVQMT-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229950003153 amsonate Drugs 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003510 anti-fibrotic effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 201000004983 autoimmune atherosclerosis Diseases 0.000 description 1
- 201000005000 autoimmune gastritis Diseases 0.000 description 1
- 201000004982 autoimmune uveitis Diseases 0.000 description 1
- 201000004988 autoimmune vasculitis Diseases 0.000 description 1
- OISFUZRUIGGTSD-LJTMIZJLSA-N azane;(2r,3r,4r,5s)-6-(methylamino)hexane-1,2,3,4,5-pentol Chemical compound N.CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO OISFUZRUIGGTSD-LJTMIZJLSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 230000005549 barrier dysfunction Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000005873 benzo[d]thiazolyl group Chemical group 0.000 description 1
- 125000005872 benzooxazolyl group Chemical group 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- SVXPPSFKJQWISH-UHFFFAOYSA-N benzyl carbamoperoxoate Chemical compound NC(=O)OOCC1=CC=CC=C1 SVXPPSFKJQWISH-UHFFFAOYSA-N 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 201000007180 bile duct carcinoma Diseases 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 230000001587 cholestatic effect Effects 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- ACYGYJFTZSAZKR-UHFFFAOYSA-J dicalcium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ACYGYJFTZSAZKR-UHFFFAOYSA-J 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 229940009662 edetate Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 229950000206 estolate Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940013317 fish oils Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 125000004615 furo[2,3-b]pyridinyl group Chemical group O1C(=CC=2C1=NC=CC2)* 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 201000011200 hepatorenal syndrome Diseases 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 230000008944 intestinal immunity Effects 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 208000008275 microscopic colitis Diseases 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 102000004233 multidrug resistance protein 3 Human genes 0.000 description 1
- 108090000743 multidrug resistance protein 3 Proteins 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 208000004995 necrotizing enterocolitis Diseases 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical compound C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-N 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 239000006014 omega-3 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003585 oxepinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000006611 pharmacological activation Effects 0.000 description 1
- 125000001828 phenalenyl group Chemical group C1(C=CC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 230000008741 proinflammatory signaling process Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001012 protector Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- STWNGMSGPBZFMX-UHFFFAOYSA-N pyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1.NC(=O)C1=CC=CN=C1 STWNGMSGPBZFMX-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical compound C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
Definitions
- the present invention is directed to modulators of a nuclear hormone receptor, famesoid X receptor (FXR), useful in the treatment of diseases or disorders associated with FXR proteins.
- FXR famesoid X receptor
- the invention is related to compounds and compositions which modulate FXR, methods of treating diseases or disorders associated with FXR, and methods of synthesis of these compounds.
- FXR is a ligand-activated transcription factor. Upon binding of a ligand, FXR either binds to DNA at the FXR response elements (FXREs) as a monomer, or forms a heterodimer with retinoid X receptor (RXR) and then binds to FXREs, regulating the transcription of a variety of target genes.
- FXREs FXR response elements
- RXR retinoid X receptor
- FXR target genes that are involved in a wide range of physiological functions including bile acid homeostasis (i.e., BACS, BAAT, BSEP, FGF15/19, etc.), cholesterol and lipoprotein metabolism (i.e., Apolipoprotein C-I, II, IV, Apolipoprotein E, MDR3, Human complement C3, ApoA-1, hepatic lipase, SREPB-1c), glucose metabolism ( i.e., PEPCK, GSK3, AKR1B7, GLUT4, G6Pase), and xenobiotics metabolism ( i.e., GST ⁇ 3, GST ⁇ 4, GST ⁇ 1, GST ⁇ 3, SULT1A1, SULT1A2).
- BACS bile acid homeostasis
- BAAT i.e., BAAT, BSEP, FGF15/19, etc.
- cholesterol and lipoprotein metabolism i.e., Apolipoprotein C-I, II, IV, Apolipoprotein E, M
- FXR a regulator of cellular inflammatory and immune responses.
- Activation of FXR can provide anti-inflammatory effects by negative regulation of nuclear factor ⁇ B (NF ⁇ B) pathway, reducing the expression of NF ⁇ B and the many pro-inflammatory cytokines associated with this pathway
- NF ⁇ B nuclear factor ⁇ B
- Moschetta, A. “Deciphering the nuclear bile acid receptor FXR paradigm, " Nucl. Recept. Signal., 2010, 8, e005 ; Huang, W., et al., "FXR: a metabolic regulator and cell protector," Cell Res., 2008, 1087-1095 ).
- FXR plays a key role in the synthesis, transport and metabolism of bile acids (BAs) and the many physiological and pathophysiological conditions that involve BAs.
- BAs bile acids
- activation of FXR has been shown to lead to the increased expression of short heterodimer partner (SHP), which in turn inactivates liver receptor homolog-1 (LRH-1) and inhibits the cholesterol 7- alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in the first step of biosynthesis of primary bile acids from cholesterol, thereby reduces the production of bile acids.
- SHP short heterodimer partner
- LH-1 liver receptor homolog-1
- CYP7A1 cholesterol 7- alpha-hydroxylase
- FXR farnesoid Activation of FXR in the liver has also been shown to downregulate transporters like Na-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting peptides (OATPs) preventing the uptake of bile acids to liver.
- NTCP Na-taurocholate co-transporting polypeptide
- OATPs organic anion-transporting peptides
- FXR has also been shown to play an important role in the inflammation control of various liver and intestinal diseases ( Shaik, F. B., et al., "Role of farnesoid X receptor in inflammation and resolution," Inflamm. Res. 2015, 64, 9-20 ). Activation of FXR has been shown to repress the NF ⁇ B pathway, a prototypical proinflammatory signaling pathway, and inhibit the expression of key cytokines such as TNF ⁇ , IL-1 ⁇ , and IL-6.
- proinflammatory cytokines e.g., TNF ⁇ , IL-1 ⁇ , IFN ⁇
- profibrotic genes i.e., Collagen ⁇ 1, TIMP-1, and ⁇ SMA
- Activation of FXR with FXR activators in the TNBS induced murine inflammatory bowel disease model has been shown to inhibit the above cytokines and provide protection against inflammation and fibrosis, subsequently against the development of colitis ( Vavassori, P., "The bile acid receptor FXR is a modulator of intestinal innate immunity," J. Immunol. 2009, 183, 6251-6261 ).
- FXR activators has the potential to be a treatment for a range of diseases including bile acid related disorders, metabolic syndrome, type-2-diabetes, hyperlipidemia, hypertriglyceridemia, primary biliary cirrhosis (PBC), fatty liver disease, nonalcoholic steatohepatitis (NASH), inflammatory autoimmune diseases, Crohn's disease, multiple sclerosis, atherosclerosis, hepatic and colon cancers, and other disorders.
- PBC primary biliary cirrhosis
- NASH nonalcoholic steatohepatitis
- known FXR activators have demonstrated toxicities, treatment limiting adverse effects, and other issues. For these reasons, there remains a need for novel and potent small molecule FXR activators.
- Another aspect of the invention relates to a method of treating a disease or disorder in which FXR plays a role.
- the method comprises administering to a patient in need of a treatment for diseases or disorders in which FXR plays a role an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention is directed to a method of modulating FXR.
- the method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention is directed to a method of activating FXR.
- the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention relates to a method of treating a liver disease.
- the method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention relates to a method of treating an intestinal disease.
- the method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention relates to a method of treating a kidney disease.
- the method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention relates to a method of treating an autoimmune disorder.
- the method comprises administering to a patient in need of a treatment for an autoimmune disorder an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention relates to a method of treating cancer.
- the method comprises administering to a patient in need of a treatment for cancer an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof
- compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with activating FXR.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease in which FXR plays a role.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a liver disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an intestinal disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a kidney disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an autoimmune disorder.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating cancer.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease associated with activating FXR.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease in which FXR plays a role.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a liver disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an intestinal disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a kidney disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of an autoimmune disorder.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of cancer.
- the present invention further provides methods of treating a disease or disorder associated with modulation of FXR including, but not limited to, liver diseases, intestinal diseases, kidney disease, autoimmune disorders, or cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- a disease or disorder associated with modulation of FXR including, but not limited to, liver diseases, intestinal diseases, kidney disease, autoimmune disorders, or cancer, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the present invention provides activators of FXR that are therapeutic agents in the treatment of diseases, such as liver diseases, intestinal diseases, kidney disease, autoimmune disorders, and cancer.
- diseases such as liver diseases, intestinal diseases, kidney disease, autoimmune disorders, and cancer.
- the present invention provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with the modulation of FXR.
- the present invention relates to compounds and compositions that are capable of modulating the activity of FXR.
- the invention features methods of treating, preventing or ameliorating a disease or disorder in which FXR plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the methods of the present invention can be used in the treatment of a variety of FXR dependent diseases and disorders by increasing the activity of nuclear receptor FXR.
- Activation or modulation of FXR provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, liver diseases, intestinal diseases, kidney diseases, autoimmune disorders, and cancer.
- the compounds of Formula (I) are described: and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein Li, A, X 1 , X 2 , R 1 , R 2 , and R 3 are as described herein.
- an element means one element or more than one element.
- an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon).
- the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
- optionally substituted means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
- Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH 2 CN, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkenyl, (C 1 -C 6 ) alkynyl, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 )haloalkoxy, (C 3 -C 7 ) cycloalkyl, aryl, heterocycloalkyl, heteroaryl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C
- substituted means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions.
- an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
- aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
- the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
- substituents include, but are not limited to, -H, -halogen, -O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 ) alkyl,-C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 ) alkyl, -NH 2 , NH((C 1 -C 6 ) alkyl), N((C 1 -C 6 ) alkyl) 2 ,-S(O) 2 -(C 1 -C 6 ) alkyl, -S
- an aryl group herein defined may be fused to an unsaturated or partially saturated ring, or fused with a fully saturated ring.
- exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
- heteroaryl means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from the group consisting of N, O, and S, the remaining ring atoms being C.
- Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from the group consisting of N, O, and S.
- the aromatic radical is optionally substituted independently with one or more substituents described herein.
- Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridin
- heteroaryl groups herein defined may be fused to an unsaturated or partially saturated ring containing a heteroatom selected from N, O and S; or fused with a fully saturated ring containing a heteroatom selected from N, O and S.
- Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H--isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.
- Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.
- Alkyl either alone or in combination with other groups (e.g. alkoxy, haloalkyl and the like) refers to a straight or branched chain saturated, unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms.
- Examples of a (C 1 -C 6 ) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert -butyl, isopentyl, neopentyl, and isohexyl.
- "alkyl" is fully saturated.
- Alkoxy refers to a straight or branched chain saturated or unsaturated (fully or partially) hydrocarbon containing 1-12 carbon atoms containing a terminal "O" in the chain, e.g., -O(alkyl).
- alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups. In an embodiment, "alkoxy" is fully saturated.
- Alkoxyalkoxy refers to an alkoxy group as defined herein which is substituted with an alkoxy group e.g., -O(alkyl)-O-(alkyl).
- alkoxyalkoxy groups include without limitation, methoxymethoxy, ethoxyethoxy, propoxymethoxy, or ethoxymethoxy.
- Alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
- the "alkenyl” group contains at least one double bond in the chain.
- the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
- alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
- An alkenyl group can be unsubstituted or substituted.
- Alkenyl, as herein defined may be straight or branched.
- Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
- the "alkynyl” group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propanyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
- An alkynyl group can be unsubstituted or substituted.
- Cycloalkyl or “carbocyclyl” means monocyclic or polycyclic saturated or unsaturated (fully or partially) non-aromatic carbon rings containing 3-18 carbon atoms.
- Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof.
- a C 3 -C 8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms.
- a cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane). In an embodiment, "cycloalkyl" is fully saturated.
- Heterocyclyl or “heterocycloalkyl” monocyclic or polycyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized ⁇ electrons (aromaticity) shared among the ring carbon or heteroatoms.
- heterocycloalkyl comprises one or two 4- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl.
- the heterocycloalkyl ring structure may be substituted by one or more substituents.
- heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
- "heterocycle” or “heterocycloalkyl” is fully saturated.
- hydroxyalkyl means an alkyl group as defined above, where the alkyl group is substituted with one or more -OH groups.
- hydroxy alkyl groups include HO-CH 2 -, HO-CH 2 -CH 2 - and CH 3 -CH(OH)-.
- "hydroxyalkyl" is fully saturated.
- haloalkyl refers to an alkyl group, as defined herein, which is substituted one or more halogen.
- haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc. In an embodiment, "haloalkyl" is fully saturated.
- haloalkoxy refers to an alkoxy group, as defined herein, which is substituted one or more halogen.
- haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. In an embodiment, "haloalkoxy" is fully saturated.
- cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C ⁇ N.
- Spirocycloalkyl or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom.
- the ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
- One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
- One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g ., O, N, S, or P).
- a (C 3 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
- One or more of the carbon atoms can be substituted with a heteroatom
- "spirocycloalkyl" or “spirocyclyl” is fully saturated.
- spiroheterocycloalkyl or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperadinyl). In an embodiment, “spiroheterocycloalkyl” or “spiroheterocyclyl is fully saturated.
- GW4064 is an FXR agonist compound having the following structure.
- solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
- the term "isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
- compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
- pharmaceutically acceptable salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphtho
- a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
- an "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
- carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
- treating refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
- disorder is used herein to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
- administer refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
- prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
- autoimmune disease includes, but is not limited to, the following autoimmune diseases: Amyotrophic Lateral Sclerosis (ALS), Autoimmune Atherosclerosis, Autoimmune Diabetes Insipidus, Autoimmune Gastritis, Autoimmune Hepatitis, Autoimmune Interstitial Cystitis, Autoimmune Uveitis, Autoimmune Vasculitis, Behcet's Disease, Celiac Disease, Chronic Fatigue Syndrome, Crohn's Disease, chronic active hepatitis, Diabetes Mellitus, Multiple Sclerosis, PBC, Primary Biliary Cirrhosis, Primary Glomerulonephritis, Primary Sclerosing Cholangitis, Psoriasis, Psoriatic Arthritis, Scleroderma, Sjogren's Syndrome, Systemic Lupus Erythematosus, Ulcerative Colitis, and Vasculitis.
- ALS Amyotrophic Lateral Sclerosis
- Atherosclerosis Autoimmune Atherosclerosis
- kidney disease includes, but is not limited to the following kidney diseases: fibrotic renal disease and diabetic nephrophathy.
- liver disease includes, but is not limited to, the following liver diseases: primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intra- and extra-cholestasis, portal vein hypertension (PAH), obesity and Type 2 Diabetes.
- PBC primary biliary cirrhosis
- PSC primary sclerosing cholangitis
- NAFLD non-alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- alcoholic liver disease intra- and extra-cholestasis
- PAH portal vein hypertension
- obesity Type 2 Diabetes
- intestinal disease includes, but is not limited to the following intestinal diseases: inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, Celiac's disease and bile acid diarrhea.
- cancer includes, but is not limited to, the following cancers: hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, gastric cancer, gastric carcinoma, colon carcinoma, gastrointestinal stromal carcinoma, bile duct carcinoma, renal carcinoma, breast cancer, and Barett's esophagus, and combinations thereof.
- the present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of activating FXR, which are useful for the treatment of diseases and disorders associated with modulation of a FXR protein or receptor.
- the invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for activating FXR.
- the present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of activating FXR, which are useful for the treatment of diseases and disorders associated with modulation of a FXR protein.
- the invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for activating FXR.
- compounds of the invention have the structure of Formula (I): or a salt thereof, wherein:
- compounds of the invention have the Formula (I) wherein:
- the compounds of Formula (I) have the structure of Formula (Ia) or (Ib): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Ic) or (Id): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Ie) or (If): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Ig) or (Ih): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Ii) or (Ij): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Ik) or (Il): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Im) or (In): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Io) or (Ip): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Iq) or (Ir): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Is) or (It): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Iu) or (Iv): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Iw) or (Ix): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Iy) or (Iz): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- the compounds of Formula (I) have the structure of Formula (Iaa) or (Ibb): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.
- X 1 is CHR y or C(O) and X 2 is NR x or N + (O - )R x .
- X 1 is CHR y and X 2 is NR x or N + (O - )R x .
- X 1 is C(O) and X 2 is NR x or N + (O - )R x .
- X 1 is CHR y and X 2 is NR x .
- X 1 is C(O) and X 2 is NR x .
- X 1 is CHR y and X 2 is N + (O - )R x .
- X 1 is C(O) and X 2 is N + (O - )R x .
- X 1 is CH 2 and X 2 is NR x .
- X 1 is NR x or N + (O - )R x and X 2 is CHR y or C(O).
- X 1 is NR x and X 2 is CHR y or C(O).
- X 1 is N + (O - )R x and X 2 is CHR y or C(O).
- X 1 is NR x and X 2 is CHR y .
- X 1 is NR x and X 2 is C(O).
- X 1 is N + (O - )R x and X 2 is CHR y . In another embodiment, X 1 is N + (O - )R x and X 2 is C(O). In another embodiment, X 1 is NR x and X2 is CH2.
- L 2 is a bond. In another embodiment L 2 is-S(O) 2 -.
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 .
- A is (C 3 -C 8 ) cycloalkyl.
- A is (C 3 -C 8 ) cycloalkyl substituted with one or more R 7 .
- A is (C 6 -C 10 ) aryl.
- A is (C 6 -C 10 ) aryl substituted with one or more R 7 .
- A is phenyl optionally substituted with one or more R 7 .
- A is phenyl unsubstituted by R 7 while R 1 and R 2 are both a halogen. In another embodiment, A is phenyl unsubstituted by R 7 while R 1 and R 2 are both a Cl at the ortho positions relative to the isoxazole ring.
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 . In another embodiment, A is heterocycloalkyl comprising one or two 5-to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more R 7 .
- A is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
- A is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- A is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more R 7 .
- A is (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl or heterocycloalkyl are optionally substituted with one or more R 7 .
- A is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the aryl or heteroaryl is optionally substituted with one or more R 7 .
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl, wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
- A is (C 6 -C 10 ) aryl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the aryl or heterocycloalkyl are optionally substituted with one or more R 7 .
- B is (C 6 -C 10 ) aryl optionally substituted with one or more R 5 .
- B is heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 5 .
- B is (C 6 -C 10 ) aryl.
- B is (C 6 -C 10 ) aryl substituted with one or more R 5 .
- B is heteroaryl.
- B is heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more R 5 .
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl are substituted with one or more R 5 .
- R 1 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 1 is halogen, CN, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 1 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 1 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 1 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 1 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 1 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In another embodiment, R 1 is H, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 1 is (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 1 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 1 is H, (C 1 -C 6 ) haloalkyl, or halogen.
- R 1 is (C 1 -C 6 ) haloalkyl or halogen.
- R 2 is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 2 is halogen, CN, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 2 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 2 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 2 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 2 is H, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 2 is (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or halogen. In another embodiment, R 2 is H, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen. In yet another embodiment, R 2 is (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen.
- R 2 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more R 9 .
- R 2 is H, (C 1 -C 6 ) haloalkyl, or halogen.
- R 2 is (C 1 -C 6 ) haloalkyl or halogen.
- R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring optionally substituted with one or more R 8 .
- R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring optionally substituted with one to three R 8 .
- R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring.
- R 1 and R 2 together when attached to the same carbon atom form a (C 3 -C 8 ) spirocycloalkyl ring substituted with one to three R 8 .
- R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring optionally substituted with one or more R 8 .
- R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring optionally substituted with one to three R 8 .
- R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring.
- R 1 and R 2 together when attached to the same atom form a (C 3 -C 8 ) spiroheterocycloalkyl ring substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring optionally substituted with one or more R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring optionally substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring.
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl ring substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring.
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one or more R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring optionally substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring.
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form an aryl ring substituted with one to three R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R 8 .
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one to three R 8 .
- R 1 and R 2 on adj acent atoms together with the atoms to which they are attached form a heteroaryl ring.
- R 1 and R 2 on adjacent atoms together with the atoms to which they are attached form a heteroaryl ring substituted with one to three R 8 .
- R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one or more R 8 .
- R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring optionally substituted with one to three R 8 .
- R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring.
- R 1 and R 2 together with the atoms to which they are attached form a (C 4 -C 8 ) cycloalkyl ring substituted with one to three R 8 .
- R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R 8 .
- R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one to three R 8 .
- R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring.
- R 1 and R 2 when cycloalkyl or heterocycloalkyl, R 1 and R 2 together with the atoms to which they are attached form a heterocycloalkyl ring substituted with one to three R 8 .
- R 3 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) hydroxyalkyl, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 3 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, or. (C 1 -C 4 ) alkoxy.
- R 3 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or (C 1 -C 4 ) hydroxyalkyl.
- R 3 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, (C 1 -C 4 ) hydroxyalkyl, or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 3 is (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 3 is (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen and (C 1 -C 6 ) alkyl.
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 6 ) alkyl.
- R 4 is COOR 6a , -(CH 2 ) n -COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , -(CH 2 ) n CONH(CH 2 ) n R 6a , CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n R 6d , -(CH 2 ) n -CONR 6b SO 2 R 6d , CONR 6b SO 2 (CH 2 ) n N(CO)R 6d CONH(CH 2 ) n SO 2 R 6e , COR 6f
- R 4 is COOR 6a . In an embodiment, R 4 is -alkyl-COOR 6a . In another embodiment, R 4 is -(CH 2 ) n -COOR 6a . In an embodiment, R 4 is CONR 6b OH. In another embodiment, R 4 is CONR 6b R 6c . In yet another embodiment, R 4 is CONH(CH 2 ) n COOR 6a . In another embodiment, R 4 is CONH(CH 2 ) n SO 2 R 6e . In yet another embodiment, R 4 is CONH(CH 2 ) n COOR 6a , CONH(CH 2 ) n R 6a , -(CH 2 ) n CONH(CH 2 ) n R 6a .
- R 4 is CONH(CH 2 ) n R 6a . In yet another embodiment, R 4 is -(CH 2 ) n CONH(CH 2 ) n R 6a . In yet another embodiment, R 4 is CONR 6b SO 2 R 6d . In yet another embodiment, R 4 is -(CH 2 ) n -NR 6b C(O)R 6c . In yet another embodiment, R 4 is -(CH 2 ) n -N(OH)-C(O)R 6c . In yet another embodiment, R 4 is - alkyl-CONR 6b SO 2 R 6d . In yet another embodiment, R 4 is COR 6f , (CH 2 ) n PO(OR 6g ) 2 .
- R 4 is COO(CH 2 ) n PO(OR 6g ) 2 . In yet another embodiment, R 4 is SO 2 NR 6b (CH 2 ) n COOR 6a . In yet another embodiment, R 4 is SO 2 R 6e . In yet another embodiment, R 4 is oxo.
- R 4 is (C 3 -C 8 ) cycloalkyl optionally substituted with (CH 2 ) n COOR 6a , COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6c .
- R 4 is heterocycloalkyl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S; and said heterocycloalkyl is optionally substituted with (CH 2 ) n COOR 6a , COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6a , SO 2 R 6e .
- R 4 is or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S; and said said heteraryl is optionally substituted with (CH 2 ) n COOR 6a , COOR 6a , CONR 6b OH, CONR 6b R 6c , CONH(CH 2 ) n COOR 6a , CONR 6b SO 2 R 6d , CONH(CH 2 ) n SO 2 R 6e , COR 6f , (CH 2 ) n PO(OR 6g ) 2 , COO(CH 2 ) n PO(OR 6g ) 2 , SO 2 NR 6b (CH 2 ) n COOR 6b , SO 2 R 6 .
- R 4 is COOR 6a , CONR 6b SO 2 R 6d , or CONR 6b R 6c . In yet another embodiment, R 4 is COOR 6a , CONR 6b SO 2 R 6d , or CONH(CH 2 ) n SO 2 R 6e . In another embodiment, R 4 is COOR 6a , CONR 6b SO 2 R 6d , or CONH(CH 2 ) n COOR 6a . In yet another embodiment, R 4 is COOR 6a , CONR 6b SO 2 R 6d , or heterocycloalkyl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- R 4 is COOR 6a , CONR 6b SO 2 R 6d , CONR 6b R 6c , or heterocycloalkyl comprising one 5- to 7-membered ring and 1-4 heteroatoms selected from the group consisting of N, O and S.
- R 4 is COOR 6a , CONR 6b SO 2 R 6d , or heterocycloalkyl comprising one 5- to 7-membered ring and 1-4 heteroatoms selected from the group consisting of N, O and S.
- R 4 is CONH(CH 2 ) n COOR 6a or CONH(CH 2 ) n SO 2 R 6e .
- R 4 is CONR 6b R 6c or CONH(CH 2 ) n COOR 6a . In another embodiment, R 4 is CONR 6b SO 2 R 6d or CONH(CH 2 ) n SO 2 R 6e .
- n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 4.
- R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, CN, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl,
- R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) haloalkoxy.
- R 5 is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, and (C 1 -C 6 ) haloalkoxy.
- the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected
- R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl.
- R 5 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or (C 1 -C 4 ) haloalkoxy.
- R y is H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy or halogen.
- R y is H.
- R y is methyl.
- R y is ethyl.
- R y is CF 3.
- R y is (C 1 -C 6 ) alkyl.
- R y is (C 1 -C 6 ) haloalkyl.
- R y is alkoxyalkyl.
- R 6a is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl
- R 6a is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
- R 6a is H, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and ⁇ OH.
- R 6a is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6a is H or (C 1 -C 4 )
- R 6b is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy
- R 6b is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
- R 6b is H, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6b is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6b is H or (C 1 -C 4 )
- R 6c is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy
- R 6c is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
- R 6c is H, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6c is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6c is H or (C 1 -C 4 )
- R 6d is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, COOH, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) al
- R 6d is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6
- R 6d is (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl.
- R 6d is (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6d is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- the heterocycloalkyl comprises one or two 5- to 7-membered rings and
- R 6d is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6d is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more -OH. In another embodiment, R 6d is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl.
- R 6c is -OH, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) al
- R 6c is -OH, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6c is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- the heterocycloalkyl comprises one or two 5- to 7-membered rings and
- R 6e is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6e is (C 6 -C 10 ) aryl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6c is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6e is heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6e is (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl or heterocycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6e is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the aryl or heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6c is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, and -OH.
- R 6c is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl, wherein the alkyl or cycloalkyl are optionally substituted with one or more ⁇ OH.
- R 6e is (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl.
- R 6c is -OH, (C 1 -C 4 ) alkyl or (C 3 -C 8 ) cycloalkyl.
- R 6f is (C 1 -C 6 ) alkyl or (C 1 -C 6 ) haloalkyl. In another embodiment, R 6f is (C 1 -C 6 ) alkyl. In another embodiment, R 6f is methyl. In another embodiment, R 6f is (C 1 -C 6 ) haloalkyl. In another embodiment, R 6f trifluoromethyl.
- R 6g is H or (C 1 -C 6 ) alkyl optionally substituted with -O-CO-(C 1 -C 6 ) alkyl. In an embodiment, R 6g is H. In an embodiment, R 6g is (C 1 -C 6 ) alkyl optionally substituted with -O-CO-(C 1 -C 6 ) alkyl. In an embodiment, R 6g is -CH 2 -O-C(O)-C(CH 3 ) 3 .
- R 7 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or CN.
- R 7 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or CN.
- R 7 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- R 7 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, or (C 1 -C 4 ) alkoxy.
- R 7 is (C 1 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 1 -C 4 ) alkoxy, or halogen. In another embodiment, R 7 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
- R 7 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen. In another embodiment, R 7 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- R 8 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, or -OH.
- R 8 is halogen, or -OH.
- R 8 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, or ⁇ OH.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, halogen, or ⁇ OH.
- R 8 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or -OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or halogen.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- R 9 is (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, halogen, or -OH.
- R 9 is halogen, or -OH.
- R 9 is (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, or -OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, halogen, or ⁇ OH.
- R 9 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, or -OH.
- m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 1 or 2. In another embodiment, m is 0 or 1.
- p is 1. In another embodiment, p is 2.
- A is (C 6 -C 10 ) aryl, (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- A is (C 6 -C 10 ) aryl or (C 3 -C 8 ) cycloalkyl.
- A is (C 6 -C 10 ) aryl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- A is (C 3 -C 8 ) cycloalkyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- A is phenyl or (C 3 -C 8 ) cycloalkyl.
- A is phenyl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- A is phenyl.
- A is cyclohexyl, bicyclo[2.2.2.]octanyl, or spiro[2.5]octanyl. In yet another embodiment, A is cyclohexyl or bicyclo[2.2.2.]octanyl. In another embodiment, A is bicyclo[2.2.2.]octanyl, or spiro[2.5]octanyl. In yet another embodiment, A is cyclohexyl, bicyclo[2.2.2.]octanyl, or tetrahydropyranyl. In another embodiment, A is cyclohexyl. In yet another embodiment, A is bicyclo[2.2.2.]octanyl. In another embodiment, A is tetrahydropyranyl.
- R 1 and R 2 are each independently H, halogen, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 ) haloalkoxy.
- R 1 and R 2 are each independently H, halogen, or (C 1 -C 6 ) haloalkyl.
- R 1 and R 2 are each independently halogen or (C 1 -C 6 ) haloalkyl.
- R 1 is H and R 2 is halogen, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) haloalkoxy.
- R 1 is H and R 2 is (C 1 -C 6 ) haloalkyl or (C 1 -C 6 ) haloalkoxy. In another embodiment, R 1 is H and R 2 is (C 1 -C 6 ) haloalkyl. In yet another embodiment, R 1 is H and R 2 is (C 1 -C 6 ) haloalkoxy. In another embodiment, R 1 is halogen and R 2 is halogen, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) haloalkoxy. In yet another embodiment, R 1 is halogen and R 2 is (C 1 -C 6 ) haloalkoxy. In another embodiment, R 1 is halogen and R 2 is (C 1 -C 6 ) haloalkyl. In yet another embodiment, R 1 is halogen and R 2 is halogen.
- B is unsubstituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S.
- B is heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, substituted with one or more halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl.
- B is unsubstituted (C 6 -C 10 ) aryl.
- B is (C 6 -C 10 ) aryl optionally substituted with (C 1 -C 6 ) alkyl, halogen, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkoxy, or (C 3 -C 8 ) cycloalkyl.
- B is pyrimidinyl, furanyl, benzo[d]thiazolyl, 1-methyl-1H-benzo[d]imidazolyl, 1-methyl-1H-indolyl, benzo[d]isoxazolyl, 2,2-difluoro-1-methylindolin-3-onyl, or 7-fluoro-1-methyl-1H-benzo[d]imidazolyl, wherein each B is optionally substituted with one or more halogen, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or (C 1 -C 6 ) haloalkyl.
- R 3 is (C 3 -C 8 ) cycloalkyl optionally substituted with halogen or (C 1 -C 6 ) alkyl. In another embodiment, R 3 is (C 3 -C 8 ) cycloalkyl optionally substituted with halogen. In another embodiment, R 3 is unsubstituted (C 3 -C 8 ) cycloalkyl.
- L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 )
- L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
- L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
- L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) hal
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalk
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl
- L 1 is -(CH 2 ) p - and L 2 is a bond .
- L 1 is -(CH 2 )p-
- L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 1
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) hal
- L 1 is a -(CH 2 )p-, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4
- L 1 is -(CH 2 ) p -, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4 )
- L 1 is -(CH 2 )p- and L 2 is a bond .
- L 1 is -(CH 2 )p-
- L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
- L 1 is -(CH 2 )p-
- L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -, L 2 is a bond
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or (C 6 -C 10 ) aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is a -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 ) a
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 2 is halogen or (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is halogen or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 )
- L 1 is -(CH 2 )p-, L 2 is a bond and A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 .
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , and B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, and R 2 is halogen or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is halogen or (C 1 -C 4 ) haloalkyl, and R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
- L 1 is -(CH 2 )p-, L 2 is a bond, and A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 .
- L 1 is -(CH 2 ) p -, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , and B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 3 is (C 1 -C 4 ) alkyl or (C
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 )p-, L 2 is a bond, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 3 is (C 1 -C 4 ) alkyl or (C 3 ) alky
- L 1 is -(CH 2 )p-
- L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
- L 1 is -(CH 2 )p-
- L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C
- L 1 is -(CH 2 )p-, L 2 is a bond
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen,
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is hal
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 .
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
- L 2 is ⁇ S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 .
- L 2 is ⁇ S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 2 is ⁇ S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
- L 2 is ⁇ S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -)
- L 2 is ⁇ S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4
- L 1 is -(CH 2 ) p - and L 2 is -S(O) 2 -.
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7 .
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , H, halogen, or (C 1 -C 4 ) haloalkyl, R 2 is H, halogen, or (C 3
- L 1 is a -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl, (C 6 -C 10 ) aryl, or heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, wherein the cycloalkyl, aryl, or heterocycloalkyl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C
- L 1 is -(CH 2 ) p - and L 2 is ⁇ S(O) 2 -.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7 .
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is a -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl or (C 6 -C 10 ) aryl wherein the cycloalkyl or aryl are optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7 .
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4 ) haloalkyl.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 3 -C 8 ) cycloalkyl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, or (C 1 -C 4 ) haloalkyl
- R 2 is halogen or (C 1 -C 4 ) haloalkyl
- R 3 is (C 3 -C 7 ) cycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen or (C 1 -C 4 ) alkyl.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 .
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -, L 2 is ⁇ S(O) 2 -, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , and R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 3 is (C 1 -C 4
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 ) p -, L2 is ⁇ S(O) 2 -, A is (C 6 -C 10 ) aryl optionally substituted with one or more R 7 , B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 , R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy, and R 3 is (C 1 -C 4 )
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7 .
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5 .
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy.
- L 1 is -(CH 2 ) p -
- L 2 is -S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) hal
- L 1 is -(CH 2 ) p -
- L 2 is ⁇ S(O) 2 -
- A is heterocycloalkyl wherein the heterocycloalkyl comprises one or two 5- to 7-membered rings and 1-4 heteroatoms selected from the group consisting of N, O and S, optionally substituted with one or more R 7
- B is (C 6 -C 10 ) aryl or heteroaryl wherein the heteroaryl comprises one or two 5- or 6-member rings and 1-4 heteroatoms selected from the group consisting of N, O and S, and wherein the aryl or heteroaryl is optionally substituted with one or more R 5
- R 1 is H, halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, or (C 1 -C 4 ) haloalkoxy
- R 2 is halogen, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) halo
- Non-limiting illustrative compounds of the invention include:
- the compound is selected from the group consisting of the group consisting of:
- the compounds of Formula (I) are enantiomers. In some embodiments the compounds are the ( S )-enantiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other embodiments, the compounds of Formula (I) may be (+) or (-) enantiomers.
- the compounds of Formula (I) are diastereomers. It should be understood that all isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.
- the compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention.
- the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
- Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound.
- the compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry.
- the assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
- an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
- converting e.g., hydrolyzing
- some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
- Enantiomers can also
- the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
- All stereoisomers for example, geometric isomers, optical isomers and the like
- of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
- those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
- the compounds of Formula I may form salts which are also within the scope of this invention.
- Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.
- the present invention relates to compounds which are modulators of FXR.
- the compounds of the present invention are activators (agonists) of FXR.
- the invention is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.
- the compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
- the compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis ( T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999 ). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I).
- the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
- a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, " Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994 ).
- the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
- the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
- compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. These methods include, but are not limited to, those described below.
- Compounds of the present invention can be synthesized by following the steps outlined in General Schemes 1, 2, 3, and 4 which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
- R 3b is an alkyl group
- X is halogen (i.e., Cl, F, etc.) or another suitable leaving group (i.e., mesylate)
- PG is a protecting group (i.e., tert -butyl carbonate (BOC)).
- N-chlorosuccinimide in a solvent i.e., N,N -dimethylformamide (DMF)
- a solvent i.e., dichloromethane
- Acid 2f is treated with activating agent (i.e., 1,1'-Carbonyldiimidazole (CDI)) and then reacted with protected 3-hydroxyl-aza-bicycloheptane intermediate 2g1 or 2g2 in a solvent (i.e., DMF) optionally at elevated temperature to form ester 2h1 or 2h2.
- activating agent i.e., 1,1'-Carbonyldiimidazole (CDI)
- CDI 1,1'-Carbonyldiimidazole
- acid 2f can be converted to an acid chloride using a chlorinating agent (i.e., thienyl chloride) in a solvent (i.e., DMF) and then reacted with protected 3-hydroxyl-aza-bicycloheptane intermediate 2g1 or 2g2 in the presence of DMAP and a base (i.e., triethylamine (Et 3 N)) and in a solvent (i.e., DMF) to form ester 2h1 or 2h2.
- a chlorinating agent i.e., thienyl chloride
- a solvent i.e., DMF
- a base i.e., triethylamine (Et 3 N)
- Et 3 N triethylamine
- intermediate 2h1 or 2h2 i.e., when PG is an acid labile group, i.e., BOC
- a strong acid i.e., trifluoroacetic acid (TFA)
- a solvent i.e., dichloromethane (DCM)
- 2i1 or 2i2 and 2j wherein R 4 in reagent 2j is optionally protected, are treated with a base in a solvent and optionally at elevated temperature to afford the desired product of Formula (I) when R 4 is unprotected, or advanced intermediate 2k1 or 2k2 when R 4 is protected.
- Deprotection intermediate 2k1 or 2k2 provides the desired product of Formula (I) .
- A, B, R 1 -R 4 and L 1 are defined as in Formula (I).
- Alcohol 3a can be oxidized to the aldehyde 3e , which is further converted to the two carbon elongated ⁇ , ⁇ -unsaturated ester 3f via a standard Wittig reaction conditions (i.e., (Carboxymethyl)triphenylphosphonium bromide ethyl ester, a base (i.e., potassium tert-butoxide) and a solvent (i.e., THF)).
- a standard Wittig reaction conditions i.e., (Carboxymethyl)triphenylphosphonium bromide ethyl ester, a base (i.e., potassium tert-butoxide) and a solvent (i.e., THF)
- 3d or 3h and 3-hydroxyl-aza-bicycloheptane intermediate 2g1 are coupled using standard acylation conditions (i.e., treatment of 3h and 2g1 with DMAP and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a solvent ( i.e., DCM)) to form the ester 3i .
- Intermediate 3i can be converted to the desired product of Formula (I) as described above in steps 6 to 8 of General Scheme 1.
- Compounds of Formula (I) can also be synthesized as described above in steps 1 to 8 of General Scheme 2 and steps 6 to 8 of General Scheme 1 from hydroxyl-aza-bicycloheptane intermediate 2g2 .
- A, B, and R 1 -R 4 are defined as in Formula (I)
- Nucleophilic addition of 2g1 to 3b in the presence of a base (i.e., sodium hydride (NaH)) and in a solvent (i.e., THF) provides 4a .
- a base i.e., sodium hydride (NaH)
- a solvent i.e., THF
- Deprotection of intermediate 4a i.e., when PG is an acid labile group, i.e., BOC
- a strong acid i.e., trifluoroacetic acid (TFA)
- DCM dichloromethane
- Another aspect of the invention is directed to a method of modulating FXR.
- the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention is directed to a method of modulating FXR.
- the method comprises administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the invention is directed to a method of activating FXR.
- the method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the invention is directed to a method of activating FXR.
- the method involves administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- Another aspect of the invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
- the method comprises administering to a patient in need of a treatment for diseases or disorders in which FXR plays a role an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- Another aspect of the invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
- the method comprises administering to a patient in need of a treatment for diseases or disorders in which FXR plays a role an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- Another aspect of the invention relates to a method of modulating FXR.
- the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- Another aspect of the invention relates to a method of modulating FXR.
- the method comprises administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- Another aspect of the present invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the activation of FXR, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- Another aspect of the present invention relates to a method of treating, preventing, inhibiting, or eliminating a disease or disorder in a patient associated with the activation of FXR, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating a liver disease.
- the method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating a liver disease.
- the method comprises administering to a patient in need of a treatment for a liver disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating an intestinal disease.
- the method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating an intestinal disease.
- the method comprises administering to a patient in need of a treatment for an intestinal disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating a kidney disease.
- the method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating a kidney disease.
- the method comprises administering to a patient in need of a treatment for a kidney disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating an autoimmune disease.
- the method comprises administering to a patient in need of a treatment for an autoimmune disease an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating an autoimmune disease.
- the method comprises administering to a patient in need of a treatment for an autoimmune disease an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating cancer.
- the method comprises administering to a patient in need of a treatment for cancer an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the present invention relates to a method of treating, preventing, inhibiting, or eliminating cancer.
- the method comprises administering to a patient in need of a treatment for cancer an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a disease or disorder in which FXR plays a role.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a disease or disorder in which FXR plays a role.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a liver disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a disease associated with activating FXR.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a liver disease.
- the present invention relates to a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of an intestinal disease.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of an intestinal disease.
- the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of a kidney disease.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of a kidney disease.
- the present invention relates to a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of an autoimmune disorder.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of an autoimmune disorder.
- the present invention relates to a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment, prevention, inhibition, or elimination of cancer.
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment, prevention, inhibition, or elimination of cancer.
- Another aspect of the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder or cancer.
- Another aspect of the present invention relates to the use of a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder in which FXR plays a role.
- the disease or disorder is a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder or cancer.
- the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a liver disease.
- the present invention relates to the use of a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a liver disease.
- the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an intestinal disease.
- the present invention relates to the use of a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an intestinal disease.
- the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a kidney disease.
- the present invention relates to the use of a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a kidney disease.
- the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an autoimmune disease.
- the present invention relates to the use of a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating an autoimmune disease.
- the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a cancer.
- the present invention relates to the use of a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, in the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a cancer.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with activating FXR.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease associated with activating FXR.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease in which FXR plays a role.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a disease in which FXR plays a role.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a liver disease.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a liver disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an intestinal disease.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating an intestinal disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a kidney disease.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating a kidney disease.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating an autoimmune disorder.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating an autoimmune disorder.
- Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating cancer.
- Another aspect of the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier, for use in the manufacture of a medicament for treating cancer.
- the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a liver disease.
- the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of an intestinal disease.
- the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a kidney disease.
- the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of an autoimmune disorder.
- the present invention relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a cancer.
- the present invention also relates to the use of an activator of FXR for the preparation of a medicament used in the treatment, prevention, inhibition, or elimination of a disease or condition in which FXR plays a role, wherein the medicament comprises a compound of Formula (I).
- the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by FXR, wherein the medicament comprises a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
- the disease or condition is selected from the group consisting of liver disease, intestinal disease, kidney disease, an autoimmune disorder, or cancer.
- the disease can be any disease including, but not limited to, Alagille syndrome (ALGS), atherosclerosis, biliary atresia, Byler disease, gallstone disease, hyperlipidemia, hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, obesity, type-2 diabetes mellitus, and gastric cancer.
- AGS Alagille syndrome
- atherosclerosis atherosclerosis
- biliary atresia Byler disease
- gallstone disease gallstone disease
- hyperlipidemia hepatocellular carcinoma
- hepatocellular adenoma cholangiocarcinoma
- colorectal cancer colorectal adenoma
- the liver disease can be any liver diseases, including, but not limited to, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, intra- and extra-cholestasis, biliary atresia, portal vein hypertension (PAH), spontaneous bacterial peritonitis (SBP), acute decompensation liver failure, hepatorenal syndrome and hepatic encephalopathy.
- PBC primary biliary cirrhosis
- PSC primary sclerosing cholangitis
- NAFLD non-alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- alcoholic liver disease intra- and extra-cholestasis
- biliary atresia portal vein hypertension
- PAH portal vein hypertension
- SBP spontaneous bacterial peritonitis
- the intestinal disease can be any intestinal disease, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, proctitis, pouchitis, Celiac's disease and bile acid diarrhea.
- the disease is an intestinal permeability disease, disorder or condition mediated by tight junction dysfunction.
- the disease, disorder or condition is gastric ulcers, infectious diarrhea, irritable bowel syndrome, functional GI diseases (IBS, IBS-C, IBS-D, IBS-M, post infectious IBS), inflammatory bowel disease (CD, UC), Celiac's, cancer (colorectal), Leaky Gut Syndrome, cystic fibrosis GI manifestations, multi-organ failure, microscopic colitis or necrotizing enterocolitis.
- compounds of the invention are used to treat one of the following disease, disorder or condition: allergy e.g. atopy, food allergy; infections e.g. respiratory infections; acute inflammation e.g. sepsis, SIRS, MOF); chronic inflammation e.g. arthritis; obesity-induced metabolic diseases e.g. NASH, diabetes, T1D/T2D, CVD; kidney disease e.g. chronic kidney disease, diabetic kidney disease; heart disease e.g. heart failure, congestive heart failure; liver disease e.g. cirrhosis, NASH, NAFLD, steatosis, PSC, PBC, portal hypertension; autoimmune disease e.g.
- type 1 diabetes, celiac disease, multiple sclerosis, IBD, ankylosing spondylitis, RA, lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, Crohn's disease, ulcerative colitis, urticaria (hives) and Raynaud's syndrome; neurological e.g. schizophrenia, autism spectrum disorders, multiple sclerosis, hepatic encephlopathy; and chronic alcoholism
- the kidney disease can be any kidney disease, including, but not limited to, fibrotic renal disease and diabetic nephrophathy.
- the autoimmune disorder can be any autoimmune disorder, including, but not limited to, inflammatory bowel disease, autoimmune hepatitis, autoimmune liver disease (primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)), and multiple sclerosis.
- inflammatory bowel disease autoimmune hepatitis
- autoimmune liver disease primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)
- PBC primary biliary cirrhosis
- PSC primary sclerosing cholangitis
- the cancer can be any cancer including, but not limited to, a cancer is selected from the group consisting of hepatocellular carcinoma, hepatocellular adenoma, cholangiocarcinoma, colorectal cancer, colorectal adenoma, ileal adenoma, renal cancer, oesophageal cancer, or gastric cancer.
- the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, of the present invention and a pharmaceutically acceptable carrier used for the treatment of diseases including, but not limited to liver diseases, intestinal diseases, kidney diseases, autoimmune disorders or cancer.
- compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
- the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
- a disease or disorder in which FXR plays a role including a liver disease, an intestinal disease, a kidney disease or an autoimmune disorder comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I).
- One therapeutic use of the compounds or compositions of the present invention which activate FXR is to provide treatment to patients or subjects suffering from a liver disease, an intestinal disease, a kidney disease, an autoimmune disorder, or cancer.
- the disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
- Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
- compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
- injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
- they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
- Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also
- Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
- the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
- a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
- Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
- the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
- the disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
- Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
- a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.
- Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
- the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
- Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
- Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
- a polymer e.g., a polycarboxylic acid polymer, or a polyacrylate.
- Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
- Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
- compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
- the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
- compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
- the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
- a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
- Effective dosage amounts of the disclosed compounds when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition.
- Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses.
- the compositions are in the form of a tablet that can be scored.
- Example 1 Intermediate. Benzyl (1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (C-1) and (1S,4R,6S)-Benzyl 6-hydroxy-2-aza-bicyclo[2.2.1]heptane-2-carboxylate (C-2)
- Example 2 Intermediate. Benzyl (1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (C-4) and Benzyl (1R,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (C-5)
- Example 3 Intermediates. Benzyl (1R,4R,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (C-4) and Benzyl (1R,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (C-5)
- the resulting white suspension was filtered through a Celite pad and the pad was washed with anhydrous THF (250.0 mL).
- the clear filtrate was cooled to 0 °C and then treated with trimethylamine (12.8 mL, 91.6 mmol) and CbzCl (10.3mL, 68.7 mmol).
- the reaction mixture was slowly warmed to room temperature and stirred for 48 hours.
- the white precipitate was filtered and the resulting clear filtrate solution was concentrated to dryness.
- the mixture was stirred at 0 °C for 2 h, and then at 40 °C overnight
- the reaction mixture was cooled to 0 °C, and a second batch of NaSCN (12.2 g, 150.49 mmol, 5.0 equiv.) was added, followed by the dropwise addition of a solution of bromine (9.6 g, 60.07 mmol, 2.0 equiv.) in AcOH (50 mL) over 1 hr.
- the reaction mixture was stirred at 0 °C for 2 h, and then at 40 °C for 3 days.
- the resulting mixture was diluted with 200 mL of water and the pH value of the aqueous solution was adjusted to 9 with sodium hydroxide.
- methyl 4-amino-3-methylbenzoate A-6a (10.0 g, 60.54 mmol, 1.0 equiv.), AcOH (200 mL), and NaSCN (19.6 g, 4.0 equiv.) followed by the dropwise addition of a solution of bromine (9.7 g, 60.70 mmol, 1.0 equiv.) in AcOH (100 mL) at 0 °C.
- the resulting mixture was stirred at 30 °C for 16 h and then quenched by the addition of 500 mL of ice water.
- the pH value of the aqueous solution was adjusted to 9 using sodium hydroxide.
- 6-bromo-1H-indole-3-carboxylic acid A-8a (5 g, 20.83 mmol, 1.0 equiv.), N,N-dimethylformamide (150 mL), MeI (5.9 g), and sodium hydride (3.5 g, 145.83 mmol, 7.0 equiv.).
- the resulting mixture was stirred at 10-25 °C for 1 h, and then diluted with 1500 mL of H 2 O.
- the aqueous mixture was extracted with ethyl acetate (200 mL ⁇ 3) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
- N -[(2,6-dichlorophenyl) methylidene] hydroxylamine 1b 60 g, 315.74 mmol, 1.0 equiv.
- N , N -dimethylformamide 250 mL
- N-chlorosuccinimide NCS, 42.5 g, 318.28 mmol, 1.0 equiv.
- Step 8 Methyl 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate (1k)
- N-[[2-(trifluoromethyl) phenyl]methylidene]-hydroxylamine 9b (10 g, 52.87 mmol, 1.0 equiv.), N,N-dimethylformamide (50 mL), and NCS (7.5 g, 56.17 mmol, 1.06 equiv.).
- the resulting mixture was stirred at 10-25 °C for 2 h, and then diluted with 200 mL of H 2 O.
- N-hydroxy-2-(trifluoromethyl)benzene-1-carbonimidoyl chloride 9c (11.5 g, 51.44 mmol, 1.0 equiv.), ethyl 3-cyclopropyl-3-oxopropanoate 1d (12 g, 76.83 mmol, 1.49 equiv.), and TEA (50 mL) and the resulting mixture was stirred at 10-25 °C overnight.
- the reaction mixture was diluted with 200 mL of H 2 O and the pH of the aqueous solution was adjusted to 5-6 using a hydrogen chloride (aq.).
- Step 8 Methyl 2-[(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]carbonyloxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylate (9i)
- the crude product was purified by silica gel column chromatography eluting with PE:EA (0%-5%) to provide(75%) of ethyl 3-(1-fluorocyclopropyl)-3-oxopropanoate 10d as a yellow oil (volatile product, removal of solvents on rotavap should be done at low temperature).
- Step 8 Methyl 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate (10j)
- N-[bicyclo[2.2.2]octan-1-ylmethylidene]-hydroxylamine 11g (2.3 g, 15.01 mmol, 1.0 equiv.) and N,N-dimethylformamide (20 mL).
- NCS (3.1 g, 23.13 mmol, 1.50 equiv.).
- the reaction mixture was stirred for 2 h at room temperature and then 300 mL of ethyl acetate was added.
- Step 8 3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazole-4-carboxylic acid (11k)
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column 5 ⁇ m, 19 mm ⁇ 250 mm; mobile phase, water (0.05%TFA ) and ACN (82.0% ACN to 90.0% over 8 min); Detector, UV 254 nm, to provide19.7 mg (25%) of 2-[(1S,4S,5R)-5-[(3-[bicyclo[2.2.2]octan-1-yl]-5-cyclopropyl-1,2-oxazol-4-yl)carbonyloxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid 1-11 was obtained as an off-white solid.
- the aqueous mixture was extracted with ethyl acetate (200 mL x2), and the combined organic extracts were washed with brine (200 mL ⁇ 2) and concentrated.
- Step 5 Methyl 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylate (12e)
- Step 6 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid (I-12)
- reaction was then quenched by the addition of 50 mL of H 2 O and the pH value of the solution was adjusted to 3-4 using aqueous hydrogen chloride (1M).
- aqueous hydrogen chloride (1M) was extracted with ethyl acetate (30 mL ⁇ 3) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 19 mm ⁇ 250 mm; mobile phase, Water (0.05%TFA ) and ACN (56% ACN to 78% over 8 min); Detector, UV 254 nm, to provide 50.5 mg (13%) of 2-[(1S,4S,SR)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid 1-12 as an off-white solid.
- Step 3 Benzyl (1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (19c)
- the resulting mixture was diluted with 30 mL of ethyl acetate, and 30 mL of water/ice was then added.
- the aqueous mixture was extracted with ethyl acetate (30 mL ⁇ 2) and the combined organic extracts were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the resulting mixture was stirred at 50 °C for 2 h. Upon cooling to room temperature, 5 mL of H 2 O was added and the pH value of the solution was adjusted to 2 using a aqueous hydrogen chloride (1M). The aqueous mixture was extracted with 50 mL of ethyl acetate and the organic extract was washed with brine (100 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 19 mm ⁇ 250 mm; mobile phase, Water (0.05%TFA ) and ACN (63.0% to 78.0% over 8 min); Detector, UV 254 nm, to provide 80.3 mg (51%) of 2-[(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid 1-19 as a colorless solid.
- the resulting mixture was stirred at room temperature for 2 h and then diluted with 10 mL of H 2 O.
- the pH value of the solution was adjusted to 2 using aqueous HCl (1M).
- the aqueous mixture was extracted with ethyl acetate (50 mL ⁇ 2) and the combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge BEH130 Prep C18 OBD Column, 150 mm ⁇ 5 um 13 nm; mobile phase, Water (0.05%TFA ) and ACN (70.0% to 85.0% over 8 min); Detector, UV 254 nm, to provide 33.8 mg (21%) of 2-[(1S,4S,5R)-5-([5-cyclopropyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid 1-20 as a colorless solid.
- Step 6 Benzyl (1S,4S,5R)-5-((3-cyclohexyl-5-cyclopropylisoxazol-4-yl)methoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate (21g).
- the mixture was diluted with of H 2 O.
- the aqueous mixture was extracted with of ethyl acetate (50 mL ⁇ 3); the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the pH value of the solution was adjusted to 3.0 using a 1M hydrogen chloride solution.
- the aqueous mixture was extracted with dichloromethane (50 mL ⁇ 3); the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 19 mm ⁇ 250 mm; mobile phase, Water (0.05%TFA ) and ACN (67.0% ACN up to 83.0% in 8 min); Detector, UV 254nm.
- N-(tetrahydropyran-4-ylmethylidene)-hydroxylamine 23b 200 mg, 1.55 mmol, 1.0 equiv.
- N,N-dimethylformamide 2 mL
- NCS 200 mg, 1.50 mmol, 1.0 equiv.
- N-hydroxyox-4-carbonimidoyl chloride 23c (2.4 g, 14.67 mmol, 1.0 equiv.) in tetrahydrofuran (20 mL) was then added dropwise at 0°C and the resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with 100 mL of ethyl acetate and the organic extract was washed with brine (100 mL) and concentrated under reduced pressure. The resulting solid was dried in an oven under reduced pressure to afford 3 g (77%) of ethyl 5-cyclopropyl-3-(oxan-4-yl)-1,2-oxazole-4-carboxylate 23d as a crude yellow oil. The crude product was carried onto the next step without further purification.
- the resulting mixture was stirred at room temperature for 1h, and then quenched by the addition of water/ice.
- the aqueous mixture was diluted with 20 mL of ethyl acetate, and further extracted with ethyl acetate (50 mL ⁇ 2).
- the combined organic extracts were washed with brine (100 mL x2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the resulting mixture was stirred at 2 5°C overnight, and then diluted with 2 mL of H 2 O.
- the pH of the aqueous mixture was adjusted to 2 using aqueous HCl (1M).
- the aqueous mixture was extracted with ethyl acetate (50 mL) and the organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column, 19 mm ⁇ 250 mm; mobile phase, Water (0.05%TFA ) and ACN (50.0% 70.0% over 8 min); Detector, UV 254 nm, to provide 36.6 mg (54%) of 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(oxan-4-yl)-1,2-oxazol-4yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid 1-23 as a colorless solid.
- the resulting mixture was stirred at room temperature for 2 h and then quenched by the addition of 5 mL of water/ice.
- the aqueous mixture was extracted with 200 mL of ethyl acetate and the organic extract was washed with brine (30 mL x4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
- the crude product was purified by Prep-HPLC using the following conditions: Column, XBridge C18 OBD Prep Column 5 ⁇ m, 19 mm ⁇ 250 mm; mobile phase, water (0.05%TFA ) and ACN (60.0% to 80.0% over 8 min); Detector, UV 254 nm, to provide 9.5 mg (24%) of 2-[(1S,4S,5R)-5-[[3-(2,6-dichlorophenyl)-5-(1-fluorocyclopropyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid 1-24 was obtained as an off-white solid.
- Step 2 2-[(1S,4S,5R)-5-[[5-(2,6-dichlorophenyl)-3-(1-fluorocyclopropyl)-2H-pyrrol-4-yl]methoxy]-2-azabicyclo [2.2.1]heptan-2-yl]-4-(trifluoromethoxy)-1,3-benzothiazole-6-carboxylic acid (I-25)
- reaction was then quenched by the addition of 100 mL of ice/salt and the aqueous mixture was extracted with ethyl acetate (100 mL ⁇ 3). The combined organic extracts were washed with brine (100 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
- Step 4 2-[(1S,4S,5R)-5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]-6-(2H-1,2,3,4-tetrazol-5-yl)-4-(trifluoromethoxy)-1,3-benzothiazole (I-27)
- Example 36 N-(cyclopropanesulfonyl)-2-[(1S,4S,5R)-5- ⁇ [5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy)-2-azabicyclo[2.2.1]heptan-2-yl]-4-fluoro-1,3-benzothiazole-6-carboxamide (1-30)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662378625P | 2016-08-23 | 2016-08-23 | |
US201762532983P | 2017-07-14 | 2017-07-14 | |
PCT/US2017/048281 WO2018039386A1 (en) | 2016-08-23 | 2017-08-23 | Hormone receptor modulators for treating metabolic conditions and disorders |
EP17768538.5A EP3504205B1 (de) | 2016-08-23 | 2017-08-23 | Hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17768538.5A Division EP3504205B1 (de) | 2016-08-23 | 2017-08-23 | Hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen |
EP17768538.5A Division-Into EP3504205B1 (de) | 2016-08-23 | 2017-08-23 | Hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3954684A1 true EP3954684A1 (de) | 2022-02-16 |
Family
ID=59895359
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP21181833.1A Pending EP3954684A1 (de) | 2016-08-23 | 2017-08-23 | Verfahren zur herstellung von hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen |
EP17768538.5A Active EP3504205B1 (de) | 2016-08-23 | 2017-08-23 | Hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17768538.5A Active EP3504205B1 (de) | 2016-08-23 | 2017-08-23 | Hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen |
Country Status (6)
Country | Link |
---|---|
US (3) | US10793568B2 (de) |
EP (2) | EP3954684A1 (de) |
JP (3) | JP7093341B2 (de) |
CN (2) | CN110177783B (de) |
MA (2) | MA46052A (de) |
WO (1) | WO2018039386A1 (de) |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2545964A1 (de) | 2011-07-13 | 2013-01-16 | Phenex Pharmaceuticals AG | Neuartige FXR- (NR1H4)-Binde- und -Aktivitätsmodulationsverbindungen |
NZ735126A (en) | 2015-03-31 | 2022-10-28 | Enanta Pharm Inc | Bile acid derivatives as fxr/tgr5 agonists and methods of use thereof |
EP3730487B1 (de) | 2016-06-13 | 2022-04-27 | Gilead Sciences, Inc. | Azetidin abkömmlinge als fxr(nr1h4)-modulierende verbindungen |
CA2968836A1 (en) | 2016-06-13 | 2017-12-13 | Gilead Sciences, Inc. | Fxr (nr1h4) modulating compounds |
TW201808283A (zh) | 2016-08-05 | 2018-03-16 | 廣東東陽光藥業有限公司 | 含氮三環化合物及其在藥物中的應用 |
US11091482B2 (en) | 2016-08-23 | 2021-08-17 | Ardelyx, Inc. | Isoxazolyl-carbonyloxy azabicyclo[3.2.1]octanyl compounds as FXR activators |
MA46052A (fr) * | 2016-08-23 | 2021-03-17 | Ardelyx Inc | Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques |
MX2019003790A (es) | 2016-10-04 | 2019-09-26 | Enanta Pharm Inc | Analogos de isoxazol como agonistas de fxr y metodos de uso de los mismos. |
US10597391B2 (en) | 2016-10-26 | 2020-03-24 | Enanta Pharmaceuticals, Inc. | Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof |
KR20190126920A (ko) | 2017-03-28 | 2019-11-12 | 길리애드 사이언시즈, 인코포레이티드 | 간 질환을 치료하기 위한 치료 조합물 |
AU2018298253B2 (en) * | 2017-07-06 | 2020-11-19 | Xuanzhu Biopharmaceutical Co., Ltd. | FXR receptor agonist |
WO2019055808A1 (en) * | 2017-09-14 | 2019-03-21 | Ardelyx, Inc. | HORMONE RECEPTOR MODULATORS FOR THE TREATMENT OF MUTAGENIC AND FIBROTIC METABOLIC CONDITIONS AND DISORDERS |
US10689391B2 (en) | 2017-12-12 | 2020-06-23 | Enanta Pharmaceuticals, Inc. | Isoxazole analogs as FXR agonists and methods of use thereof |
CN110128432B (zh) | 2018-02-02 | 2021-03-02 | 广东东阳光药业有限公司 | 含氮三环化合物及其在药物中的应用 |
WO2019160813A1 (en) | 2018-02-14 | 2019-08-22 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as fxr agonists and methods of use thereof |
WO2020001304A1 (zh) * | 2018-06-26 | 2020-01-02 | 轩竹(海南)医药科技有限公司 | Fxr受体激动剂 |
CN108774194A (zh) * | 2018-07-23 | 2018-11-09 | 南京纽邦生物科技有限公司 | 一种2-[(2-苯并噻唑甲基)硫基]-6-乙氧基苯并噻唑及其中间体的制备方法 |
BR112021002050A2 (pt) * | 2018-08-08 | 2021-05-04 | Inorbit Therapeutics Ab | composto, composição farmacêutica, e, métodos para modular e ativar um receptor farsenoide x (fxr) e para tratar e/ou prevenir uma doença ou transtorno |
EA202191566A1 (ru) | 2019-01-15 | 2021-11-01 | Джилид Сайенсиз, Инк. | Соединения, модулирующие fxr (nr1h4) |
CA3129949C (en) | 2019-02-19 | 2024-04-30 | Gilead Sciences, Inc. | Solid forms of fxr agonists |
JP7398605B2 (ja) * | 2019-04-19 | 2023-12-15 | シャンハイ インスティチュート オブ マテリア メディカ,チャイニーズ アカデミー オブ サイエンシーズ | Fxr小分子アゴニストとその調製方法および用途 |
CN111825667B (zh) * | 2019-04-19 | 2023-07-25 | 中国科学院上海药物研究所 | Fxr小分子激动剂及其制备方法和用途 |
CN111892591A (zh) * | 2019-05-06 | 2020-11-06 | 南京科技职业学院 | 一种维奈托克关键中间体的合成方法 |
WO2020231917A1 (en) | 2019-05-13 | 2020-11-19 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as fxr agonists and methods of use thereof |
CA3159261A1 (en) * | 2019-11-29 | 2021-06-03 | Sunshine Lake Pharma Co., Ltd. | Amorphous form of nitrogen-containing tricyclic compound and use thereof |
CN111303034A (zh) * | 2020-03-18 | 2020-06-19 | 徐州圣元化工有限公司 | 一种3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸的制备方法 |
WO2021198981A1 (en) | 2020-04-01 | 2021-10-07 | Janssen Biopharma, Inc. | Antiviral compounds and uses thereof |
CN111943848B (zh) * | 2020-08-19 | 2023-05-05 | 苏州旺山旺水生物医药有限公司 | 一种elexacaftor中间体的制备方法及其应用 |
PE20240118A1 (es) * | 2020-12-30 | 2024-01-22 | Terns Pharmaceuticals Inc | Compuestos y metodos para modular elfxr |
WO2022179636A1 (zh) * | 2021-02-27 | 2022-09-01 | 轩竹生物科技股份有限公司 | Fxr受体激动剂的晶型 |
CN113024552B (zh) * | 2021-03-26 | 2022-08-05 | 厦门市博瑞来医药科技有限公司 | 一类新型非甾体fxr激动剂的合成及其应用 |
CN114773162A (zh) * | 2022-03-27 | 2022-07-22 | 江苏壹药新材料有限公司 | 一种4-(3-羟基丙烯基)-2-三氟甲基苯酚的合成方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012087519A1 (en) * | 2010-12-20 | 2012-06-28 | Irm Llc | Compositions and methods for modulating fxr |
WO2016127924A1 (en) * | 2015-02-13 | 2016-08-18 | Sunshine Lake Pharma Co., Ltd. | Tricyclic compounds and uses thereof in medicine |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5262564A (en) | 1992-10-30 | 1993-11-16 | Octamer, Inc. | Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents |
TW200906823A (en) | 2007-07-16 | 2009-02-16 | Lilly Co Eli | Compounds and methods for modulating FXR |
JP2014500318A (ja) | 2010-12-20 | 2014-01-09 | アイアールエム・リミテッド・ライアビリティ・カンパニー | ファルネソイドx受容体を調節するための組成物および方法 |
CN103391937A (zh) | 2010-12-20 | 2013-11-13 | Irm责任有限公司 | 用于调控法尼醇x受体的组合物和方法 |
WO2016097933A1 (en) | 2014-12-18 | 2016-06-23 | Novartis Ag | Azabicyclooctane derivatives as fxr agonists for use in the treatment of liver and gastrointestinal diseases |
MA46052A (fr) * | 2016-08-23 | 2021-03-17 | Ardelyx Inc | Modulateurs du récepteur hormonal pour le traitement d'états et de troubles métaboliques |
AU2018298253B2 (en) * | 2017-07-06 | 2020-11-19 | Xuanzhu Biopharmaceutical Co., Ltd. | FXR receptor agonist |
-
2017
- 2017-08-23 MA MA046052A patent/MA46052A/fr unknown
- 2017-08-23 EP EP21181833.1A patent/EP3954684A1/de active Pending
- 2017-08-23 JP JP2019511374A patent/JP7093341B2/ja active Active
- 2017-08-23 CN CN201780065305.2A patent/CN110177783B/zh active Active
- 2017-08-23 WO PCT/US2017/048281 patent/WO2018039386A1/en unknown
- 2017-08-23 US US16/327,791 patent/US10793568B2/en active Active
- 2017-08-23 MA MA055632A patent/MA55632A/fr unknown
- 2017-08-23 CN CN202310620878.4A patent/CN116854681A/zh active Pending
- 2017-08-23 EP EP17768538.5A patent/EP3504205B1/de active Active
-
2020
- 2020-08-11 US US16/990,827 patent/US20210017177A1/en not_active Abandoned
-
2022
- 2022-01-05 JP JP2022000557A patent/JP2022050527A/ja not_active Withdrawn
- 2022-07-06 US US17/858,917 patent/US20230139597A1/en active Pending
-
2024
- 2024-01-04 JP JP2024000355A patent/JP2024038260A/ja active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012087519A1 (en) * | 2010-12-20 | 2012-06-28 | Irm Llc | Compositions and methods for modulating fxr |
WO2016127924A1 (en) * | 2015-02-13 | 2016-08-18 | Sunshine Lake Pharma Co., Ltd. | Tricyclic compounds and uses thereof in medicine |
Also Published As
Publication number | Publication date |
---|---|
WO2018039386A1 (en) | 2018-03-01 |
MA46052A (fr) | 2021-03-17 |
CN110177783A (zh) | 2019-08-27 |
MA55632A (fr) | 2022-02-16 |
US10793568B2 (en) | 2020-10-06 |
CN110177783B (zh) | 2023-06-06 |
JP2024038260A (ja) | 2024-03-19 |
EP3504205B1 (de) | 2021-08-04 |
US20210017177A1 (en) | 2021-01-21 |
CN116854681A (zh) | 2023-10-10 |
EP3504205A1 (de) | 2019-07-03 |
JP2019531271A (ja) | 2019-10-31 |
JP2022050527A (ja) | 2022-03-30 |
US20190233420A1 (en) | 2019-08-01 |
US20230139597A1 (en) | 2023-05-04 |
JP7093341B2 (ja) | 2022-06-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3504205B1 (de) | Hormon-rezeptor-modulatoren zur behandlung von metabolischen bedingungen und störungen | |
JP6845897B2 (ja) | Betブロモドメイン阻害剤としてのテトラヒドロキノリン組成物 | |
US11820746B2 (en) | Aza (indole)-, benzothiophene-, and benzofuran-3-sulfonamides | |
US10370343B2 (en) | [6,6] Fused bicyclic HDAC8 inhibitors | |
TW202304878A (zh) | 含有具有縮合環之glp-1受體促效劑的醫藥組合物 | |
EP3305789A1 (de) | Stickstoffhaltiges trizyklisches derivat mit hiv-replikationshemmender wirkung | |
JP2021534240A (ja) | トランスグルタミナーゼ2(tg2)阻害剤 | |
EP3681881B1 (de) | Hormonrezeptormodulatoren zur behandlung metabolischer mutagener und fibrotischer erkrankungen und störungen | |
CN117377666A (zh) | 含有具有稠环的glp-1受体激动剂的药物组合物 | |
WO2024006781A1 (en) | Estrogen receptor alpha degraders and use thereof | |
CN117597336A (zh) | 作为造血祖细胞激酶1(hpk1)抑制剂的卤素取代的氨基氮杂-杂芳基化合物 | |
TW202417425A (zh) | 雌激素受體α降解劑及其使用方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN PUBLISHED |
|
AC | Divisional application: reference to earlier application |
Ref document number: 3504205 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20220816 |
|
RBV | Designated contracting states (corrected) |
Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20230830 |